ABSTRACT
BACKGROUND: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. OBJECTIVE: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. METHODS: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. RESULTS: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. CONCLUSION: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.
ABSTRACT
Nephrotic syndrome (NS) is defined by massive proteinuria and hypoalbuminemia, with resulting hyperlipidemia and edema. The most common cause of NS in children is idiopathic nephrotic syndrome (INS), also called nephrosis. Its annual incidence has been estimated to 1-4 per 100,000 children and varies with age, race, and geography. Many agents or conditions have been reported to be associated with INS such as infectious diseases, drugs, allergy, vaccinations, and malignancies. The disease may occur during the 1st year of life, but it usually starts between the ages of 2 and 7 years. INS is characterized by a sudden onset, edema being the major presenting symptom, but may rarely be discovered during a routine urine analysis. The disease may also be revealed by a complication such as hypovolemia, infection (pneumonia and peritonitis due to Streptococcus pneumoniae), deep-vein or arterial thromboses, and pulmonary embolism. Renal biopsy is usually not indicated in a child aged 1-10 years with typical symptoms and a complete remission with corticosteroids. Conversely, it is indicated in children under 1 year in case of macroscopic hematuria, hypertension, low C3 levels, persistent renal failure, or steroid resistance. Steroid therapy is applied in all children whatever the histopathology. Initial prednisone therapy in France consists of 60mg/m2 administered daily for 4 weeks (maximum dose, 60mg/day), followed by alternate-day prednisone with tapering doses. Eight-five to 90 % patients are steroid-responsive and may relapse, but the majority still responds to steroids over the subsequent courses. Only 1-3 % of patients who are initially steroid-sensitive subsequently become steroid-resistant. Children with primary or secondary steroid-resistance are at risk of end-stage kidney disease. Symptomatic treatment includes salt restriction, fluid restriction when natremia is less than 125 meq/L, reduction of saturated fat and carbohydrates, calcium and vitamin D supplements, anticoagulation, and vaccination. Albumin infusions are only indicated in case of complications. Diuretics should be restricted to cases of severe edema, after hypovolemia has been corrected.
Subject(s)
Nephrotic Syndrome , Child , Humans , Nephrotic Syndrome/complications , Nephrotic Syndrome/diagnosis , Nephrotic Syndrome/therapyABSTRACT
Primary nephrotic syndrome (NS) is the most common glomerular disease in children. It is characterized by massive proteinuria and hypoalbuminemia. It typically has a sudden onset and more than 70% of patients will experience at least one relapse. An immunological origin has long been postulated, although the precise molecular mechanisms underlying the disease remain debated. Steroids are the first-line therapy with cumulative dose and duration of initial treatment varying among countries. Steroid-sparing agents may be indicated in case of steroid-dependency or frequent relapses. However, no consensus exists regarding the different treatment options. These treatments are mostly suspensive and therefore, need to be prolonged for several months. Levamisole, an antihelminthic drug, also has an immunomodulatory function, and alone or in combination with steroids, it can decrease cumulative steroid dose and relapses. It is usually well tolerated, and its principal side effects are cytopenia and elevated liver enzymes. Mycophenolate mofetil is an immunosuppressive agent whose reported side effects are cytopenia and diarrhea. Calcineurin inhibitors (cyclosporine or tacrolimus) have long been used in steroid-dependent patients. Their major side effects are hirsutism, gum hypertrophy, and nephrotoxicity, leading to interstitial kidney fibrosis and chronic kidney disease. Cyclophosphamide is an efficient treatment but its gonadal toxicity is a major drawback to its use. More recent drugs such as rituximab are very effective but require hospitalization for the infusion and induce an increased risk of opportunistic infection, prolonged neutropenia, and anaphylaxis. In this review, we present the available treatments, their indications, and the side effects.
Subject(s)
Glucocorticoids/therapeutic use , Nephrotic Syndrome/drug therapy , Calcineurin Inhibitors/therapeutic use , Child , Humans , Levamisole/therapeutic use , Mycophenolic Acid/therapeutic useABSTRACT
PURPOSE: To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE). METHODS: Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia. CONCLUSION: These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.
Subject(s)
Expert Testimony , Infection Control/standards , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/therapy , Practice Guidelines as Topic , Adolescent , Adult , France , Humans , Immunocompromised Host , Infection Control/methods , Infections/diagnosis , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/immunology , Review Literature as Topic , Vaccination/standards , Young AdultABSTRACT
Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder, caused by defective transport of cationic amino acids at the basolateral membrane of epithelial cells, typically in intestines and kidneys. The SLC7A7 gene, mutated in LPI patients, encodes the light subunit (y+LAT1) of a member of the heterodimeric amino acid transporter family.The diagnosis of LPI is difficult due to unspecific clinical features: protein intolerance, failure to thrive and vomiting after weaning. Later on, patients may present delayed growth osteoporosis, hepatosplenomegaly, muscle hypotonia and life-threatening complications such as alveolar proteinosis, haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Renal involvement is also a serious complication with tubular and more rarely, glomerular lesions that may lead to end-stage kidney disease (ESKD). We report six cases of LPI followed in three different French paediatric centres who presented LPI-related nephropathy during childhood. Four of them developed chronic kidney disease during follow-up, including one with ESKD. Five developed chronic tubulopathies and one a chronic glomerulonephritis. A histological pattern of membranoproliferative glomerulonephritis was first associated with a polyclonal immunoglobulin deposition, treated by immunosuppressive therapy. He then required a second kidney biopsy after a relapse of the nephrotic syndrome; the immunoglobulin deposition was then monoclonal (IgG1 kappa). This is the first observation of an evolution from a polyclonal to a monotypic immune glomerulonephritis. Immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping is a debated complication in LPI. Our results suggest all LPI patients should be monitored for renal disease regularly.
ABSTRACT
Prophylaxis has dramatically decreased the occurrence of cytomegalovirus (CMV) infection after renal transplantation. Optimal regimens of treatment remain controversial, especially in pediatric recipients. The aim of this study was to evaluate the effectiveness of valganciclovir (VGC) versus aciclovir/valaciclovir (ACV) in a pediatric renal transplant population. Data from 101 renal transplantations were retrospectively analyzed. Except those with R-/Dstatus, all patients received prophylaxis either with ACV, n = 39 or VGC, n = 38. Incidences of positive CMV antigenemia and disease, as well as the delay in relation to the prophylaxis, were collected during at least 12 months after the end of treatment. Positive CMV antigenemia was reported in 34 patients (ACV: 16, VGC: 16, no prophylaxis: 2). CMV disease occurred in 15 patients (ACV: 5; VGC: 8) (ns). For the majority of patients under VGC, positive CMV antigenemia occurred within the year following the withdrawal of prophylaxis (VGC: 14; ACV: 5, P <0.05), whereas it occurred during prophylaxis in 11 patients under ACV versus two under VGC (P <0.05). The over-all incidence of positive CMV antigenemia was similar between ACV and VGC prophylaxis. However, VGC was more efficient to prevent early CMV infection while patients treated with ACV had less CMV infection or disease after the end of the prophylaxis.
ABSTRACT
PURPOSE: To develop French recommendations about screening and management of cardiovascular risk factors in systemic lupus erythematosus (SLE). METHODS: Thirty-nine experts qualified in internal medicine, rheumatology and nephrology have selected recommendations from a list developed based on evidence from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Experts recommended an annual screening of cardiovascular risk factors in SLE. Statins should be prescribed for primary prevention in SLE patients based on the level of LDL-cholesterol and the number of cardiovascular risk factors, considering SLE as an additional risk factor. For secondary prevention, experts have agreed on an LDL-cholesterol target of <0.7 g/L. Hypertension should be managed according to the 2013 European guidelines, using renin-angiotensin system blockers as first line agents in case of renal involvement. Aspirin can be prescribed in patients with high cardiovascular risk or with antiphospholipid antibodies. CONCLUSION: These recommendations about the screening and management of cardiovascular risk factors in SLE can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.
Subject(s)
Cardiovascular Diseases/etiology , Lupus Erythematosus, Systemic/complications , Mass Screening/methods , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/drug therapy , Evidence-Based Medicine , Expert Testimony , Guidelines as Topic , Humans , Risk Factors , Secondary PreventionABSTRACT
To determine age-related risk factors of urological and vascular complications. We performed a retrospective analysis of the data of 202 renal transplantations in 193 children between 1989 and 2007 at a single institution. Out of 193 grafts (combined renal and liver grafts were excluded), we observed urological complications in 42 cases (21.7%) leading to graft loss in one case and vascular complications in 27 cases (13.9%) leading to graft loss in seven. The urological complications were VUR (n=25, 12.4%), ureteral stricture (n=10, 5%), anastomotic leak (n=4, 2%), ureteral necrosis (n=2, 1%), and incrustative pyelitis (n=1, 0.5%). Vascular complications were arterial stricture (n=14, 7.2%), arterial thrombosis (n=4, 2%), venous thrombosis (n=2, 1%), and others (n=7). Donors aged less than six yr were a risk factor of vascular complications leading to graft loss (p=0.0001), whereas patients with PUV had more urological complications (p=0.001). Overall patient and graft survival is 93.1% and 84% at five yr, respectively. Surgical complications remain a major cause of graft loss (12%) and morbidity in children's kidney transplantation (38.9%). Young age of donors is the major risk factor of early graft loss as a result of vascular complication. However, donor selection based on age is limited by the shortage of organs.
Subject(s)
Kidney Transplantation , Postoperative Complications/epidemiology , Adolescent , Age Factors , Child , Child, Preschool , Graft Rejection , Graft Survival , Humans , Infant , Retrospective Studies , Risk Factors , Survival Analysis , Young AdultSubject(s)
Lupus Erythematosus, Systemic/mortality , Adolescent , Bacterial Infections , Cause of Death , Child , Child, Preschool , Encephalitis , Female , France , Humans , Male , Pancreatitis , Pulmonary Embolism , Retrospective StudiesABSTRACT
The aim of this study was to assess the prevalence of de novo malignancy after solid organ transplantation in childhood. A retrospective questionnaire-based survey was sent to 9 referral centers for pediatric organ transplantation in France. Among 1326 children who underwent solid organ transplantation since 1996, 80 (6%) presented with de novo malignancy posttransplantation during childhood: posttransplant lymphoproliferative disease was the most common (5% of pediatric recipients) comprising 80% of all tumors, with a disproportionately high prevalence among combined liver and small bowel recipients (18%). Various solid tumors were observed mainly among kidney recipients. No skin cancer was reported.
Subject(s)
Neoplasms/epidemiology , Organ Transplantation/adverse effects , Child , Humans , Incidence , Intestine, Small/transplantation , Liver Transplantation/adverse effects , Lymphoproliferative Disorders/epidemiology , Prevalence , Retrospective Studies , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To define prospectively the incidence of renal parenchymal lesions in the siblings of patients treated at one institution for primary vesico-ureteric reflux (VUR). PATIENTS AND METHODS: From January 1997 to October 1998, a prospective study including renal scintigraphy (using dimercaptosuccinic acid, DMSA) and a radionuclide cystogram was proposed systematically to the asymptomatic siblings of children treated for primary VUR. The radionuclide cystograms were interpreted as showing the presence or absence of VUR and the DMSA scan as symmetrical or asymmetrical differential function, with or with no renal defect. RESULTS: Fifty-five families gave informed consent, of whom 46 completed the study (eight refused secondarily and one was omitted by exclusion criteria), representing 46 symptomatic patients and 65 siblings. There were 17 siblings with VUR (26%) including two of 13 infants and 15 of 52 children aged > 18 months. One radionuclide cystogram failed. Of the 17 refluxing siblings, four had a history of symptomatic urinary tract infection; 62 of the 65 siblings had a DMSA scan, of which 56 were normal and six (10%) showed abnormalities (five asymmetrical differential function and one parenchymal defect). Only one of these six patients had VUR at the time of the evaluation and only one had a small kidney detected by ultrasonography on one side (and no VUR). There were no adverse effects associated with screening. CONCLUSION: This study confirms a significant overall incidence of VUR (26%) in the asymptomatic siblings of patients treated for primary VUR. From the results of the DMSA scan (only one sibling had a parenchymal defect), the systematic screening of asymptomatic siblings does not appear to be beneficial.
Subject(s)
Kidney Diseases/diagnostic imaging , Vesico-Ureteral Reflux/diagnostic imaging , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Kidney Diseases/genetics , Male , Pedigree , Prospective Studies , Radionuclide Imaging , Radiopharmaceuticals , Technetium Tc 99m Dimercaptosuccinic Acid , Vesico-Ureteral Reflux/geneticsABSTRACT
BACKGROUND: Donor splice-site de novo heterozygous mutations in intron 9 of the Wilms' tumor gene (WT1) have been reported in Frasier syndrome, which is defined by the association of focal and segmental glomerulosclerosis (FSGS), male pseudohermaphroditism, and gonadoblastoma. These splice-site mutations alter the WT1 alternative splicing leading to two WT1 isoforms, with (+) or without (-) three amino acids, lysine-threonine-serine (KTS), between zinc fingers 3 and 4. The aim of this work was to investigate the possibility that some cases of primary steroid-resistant nephrotic syndrome associated with FSGS may be caused by WT1 splice-site mutations. METHODS: We analyzed WT1 exons 8 and 9 and the surrounding exon/intron boundary DNA sequences in 37 children with nonfamilial primary steroid-resistant nephrotic syndrome. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the relative ratio of +KTS/-KTS transcripts from immortalized lymphocyte RNA. RESULTS: One boy with FSGS and associated pathologies (diaphragmatic hernia, proximal hypospadias, and unilateral testicular ectopia) was found to carry the heterozygous 1228 +4 C-->T splice-site mutation. RT-PCR quantitation of the +KTS/-KTS transcripts from immortalized lymphocyte RNA of this patient showed a diminution of the +KTS/-KTS isoform ratio (0.43), which is identical to that reported in patients with Frasier syndrome. Using the same approach, healthy control subjects have +KTS/-KTS ratios ranging from 1.50 to 2.00. CONCLUSIONS: This study expands the range of the phenotypic presentation of the intron 9 splice-site WT1 mutations and adds to the already reported heterogeneity of primary steroid-resistant nephrotic syndromes. We suggest that these mutations are not likely to be a common cause of isolated steroid-resistant nephrotic syndrome, and recommend a WT1 exon 9/intron 9 splice-site study in children with primary steroid-resistant nephrotic syndrome if genital or diaphragmatic anomalies are associated. The identification of such WT1 mutations has practical implications for the management of these patients.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , DNA-Binding Proteins/genetics , Glomerulosclerosis, Focal Segmental/genetics , Mutation , Transcription Factors/genetics , Adolescent , Child , Child, Preschool , Exons , Female , Glomerulosclerosis, Focal Segmental/drug therapy , Humans , Infant , Male , RNA Splicing , WT1 ProteinsSubject(s)
Azathioprine/therapeutic use , Erythrocytes/enzymology , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/physiology , Methyltransferases/blood , Adrenal Cortex Hormones/therapeutic use , Child , Cyclosporine/therapeutic use , Drug Monitoring/methods , Drug Therapy, Combination , Female , Graft Rejection/blood , Graft Rejection/enzymology , Humans , Kidney Transplantation/immunology , MaleSubject(s)
Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation/immunology , Mycophenolic Acid/analogs & derivatives , Adolescent , Adrenal Cortex Hormones/therapeutic use , Area Under Curve , Child , Cyclosporine/therapeutic use , Drug Therapy, Combination , Humans , Immunosuppressive Agents/therapeutic use , Metabolic Clearance Rate , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use , ReoperationABSTRACT
Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5-124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 microg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 microg.h/ml for MPA and 1,515+/-722 microg.h/ml for MPAG, and the apparent oral clearance was 11.7+/-7.0 and 0.5+/-0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 microg/ml and 75.2+/-32.9 microg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.
Subject(s)
Glucuronates/blood , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Abdominal Pain/chemically induced , Adolescent , Child , Cyclosporine/administration & dosage , Diarrhea/chemically induced , Glucuronides , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Mycophenolic Acid/adverse effects , Mycophenolic Acid/blood , Mycophenolic Acid/pharmacokinetics , Prospective StudiesABSTRACT
Simultaneous natural changes in lipoprotein(a) [Lp(a)] and plasminogen occur in the nephrotic syndrome and offer a unique opportunity to investigate their effects on plasminogen activation under conditions fashioned in vivo. Plasminogen, Lp(a), and apolipoprotein(a) in plasma were characterized, and their competitive binding to carboxy-terminal lysine residues of fibrin and cell membrane proteins was determined in nephrotic children during a flare-up of the disease (61 cases) and after 6 weeks (33 cases) and 6 months (42 cases) of remission. Low plasminogen concentrations (median 1.34 micromol/L, range 0.39 to 1.96 micromol/L) and high Lp(a) levels (median 0.27 g/L, range 0.07 to 2. 57 g/L) were detected at flare-up. These changes were associated with an increased Lp(a) binding ratio onto fibrin (3.13+/-0.48) and cells (1.53+/-0.24) compared with binding ratios of control children (1.31+/-0.19 and 1.05+/-0.07, respectively) with normal plasminogen and low Lp(a) (median 0.071 g/L). After 6 weeks and 6 months of remission, the values for net decrease in Lp(a) binding to fibrin were 1.7+/-0.22 (after 6 weeks) and 1.88+/-0.38 (after 6 months) and were correlated with low Lp(a) concentrations (median 0.2 g/L, range 0.07 to 0.8 g/L; and median 0.12 g/L, range 0.07 to 1.34 g/L) and inversely associated with increased plasminogen levels (median 1.82 micromol/L, range 1.4 to 2.1 micromol/L; and median 1.58 micromol/L, range 1.1 to 2.1 micromol/L). These studies provide the first quantitative evidence that binding of Lp(a) to lysine residues of fibrin and cell surfaces is directly related to circulating levels of both plasminogen and Lp(a) and that these glycoproteins may interact as competitive ligands for these biological surfaces in vivo. This mechanism may be of relevance to the atherothrombotic role of Lp(a), particularly in nephrotic patients.
Subject(s)
Fibrin/metabolism , Genetic Variation , Lipoprotein(a)/genetics , Lipoprotein(a)/metabolism , Membrane Proteins/metabolism , Plasminogen/metabolism , Adolescent , Apolipoproteins A/blood , Apolipoproteins A/genetics , Binding, Competitive , Cell Line , Child , Child, Preschool , Female , Fibrinolysis , Humans , Infant , Lipids/blood , Male , Nephrotic Syndrome/blood , Phenotype , Serum Albumin/metabolismSubject(s)
Antibodies, Monoclonal/pharmacokinetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation/immunology , Receptors, Interleukin-2/blood , Adolescent , Antibodies, Monoclonal/therapeutic use , Basiliximab , Child , Child, Preschool , Humans , Immunosuppressive Agents/therapeutic use , Infant , Lymphocyte Count , Prospective Studies , Receptors, Interleukin-2/immunology , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/therapeutic use , Time FactorsABSTRACT
AIMS: Azathioprine is a prodrug commonly used in combination therapy to prevent allograft rejection after renal transplantation. After conversion to 6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and intraindividual variability of red blood cell thiopurine methyltransferase and 6-TGN concentrations and their relationship to the clinical effects of azathioprine in paediatric patients. METHODS: In the present study, the inter- and intraindividual variations in red blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after renal transplantation in 22 paediatric patients. RESULTS: 6-TGN concentration reached steady-state values after 6 months and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity (median: 20.8 nmol h-1 ml-1, range 7.8-34.6) and 6-TGN concentration at steady-state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 366) were not related to the occurrence of rejection episodes during the period of the study. In contrast, TPMT activity and the percentage difference in TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those that did not reject during the first 3 months or the first year following transplantation (P<0.005). CONCLUSIONS: We report a relationship between TPMT activity and occurrence of rejection in paediatric kidney transplant patients undergoing azathioprine therapy. These data suggest a link between high red blood cell TPMT activity and poor clinical outcome probably caused by rapid azathioprine catabolism.
Subject(s)
Antimetabolites/pharmacology , Azathioprine/pharmacology , Graft Rejection/metabolism , Immunosuppressive Agents/pharmacology , Kidney Transplantation , Methyltransferases/metabolism , Prodrugs/pharmacology , Child , Chromatography, High Pressure Liquid , Female , Genotype , Guanine Nucleotides/blood , Guanine Nucleotides/metabolism , Humans , Kidney Transplantation/physiology , Male , Methyltransferases/blood , Methyltransferases/genetics , Thionucleotides/blood , Thionucleotides/metabolismABSTRACT
Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6+/-1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3. 5+/-1.4 years. During treatment, mean height increased from -3.0+/-0. 9 standard deviation score (SDS) to -1.9+/-1.4 SDS (P<0.001) at the time of transplantation, corresponding to a mean height gain of +1. 2+/-0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5+/-0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: -0.5+/-0.4 SDS in patients grafted at early stages of puberty (P2-P3) and -0.15+/-0.9 SDS in patients grafted at late stages of puberty (P4-P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children.