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Biomedical subjects

Christer Holmberg

Publications and source records attributed to Christer Holmberg.

At least 19 recordsLinked to original sources
PubMed2004

Tissue expression of nephrin in human and pig.

Nephrin is a major component of the glomerular filtration barrier. Mutations in the nephrin gene (NPHS1) are responsible for congenital nephrotic syndrome of the Finnish type (NPHS1). Nephrin was at first thought to be podocyte specific, but recent studies have suggested that nephrin is also expressed in nonrenal tissues such as pancreas and CNS. We studied the expression of nephrin in human and porcine tissues at different stages of development and correlated these findings to clinical characteristics of NPHS1 children. Immunofluorescence staining and Western blotting were used to detect nephrin protein in frozen tissue samples. Polyclonal antibodies against the intracellular part of nephrin were used in these analyses. In situ hybridization was used to detect nephrin mRNA in specimens from normal human subjects and patients with NPHS1. Nephrin protein was not detected in nonrenal tissues obtained from human and porcine fetuses, newborns, and infants. Likewise, nephrin mRNA expression was not observed outside kidney glomerulus in normal or NPHS1 children. The phenotype analysis of NPHS1 children with severe nephrin gene mutations supported the findings in the tissue expression studies and revealed no impairment of the neurologic, testicular, or pancreatic function in a great majority of the patients. The studies suggest that nephrin has no major clinical significance outside the kidney.

Animals↗
PubMed2004

Serum lipids in children 3 to 5 years after kidney, liver, and heart transplantation.

Although dyslipidemia is common after solid organ transplantation (Tx), there are few long-term studies in children. We investigated the prevalence of dyslipidemia up to 5 years after Tx in 125 children on triple immunosuppression with one of three different well-functioning grafts, kidney, liver, and heart, and 181 controls. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations were measured annually. Low-density lipoprotein cholesterol concentrations were also calculated. The risk factors for dyslipidemia were determined at 3 years. There was a high prevalence of hypertriglyceridaemia in all three groups, 50% in the kidney transplantation (KTx) and heart transplantation (HTx) groups and 30% in the liver transplantation (LTx) group. In addition, 50% of KTx patients had high TC. In the Tx groups taken together, the following independent associations were observed: KTx and high pre-Tx TC were associated with high TC, high trough concentration of blood cyclosporine with low HDL-C, and older age at Tx accounted for higher TG. Dyslipidemia, especially hypertriglyceridaemia, was common 3-5 years after Tx. The aetiology is multifactorial and depends on the transplanted organ.

Body Height↗
PubMed2004

Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression.

BACKGROUND: In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long-term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single-dose pharmacokinetics and short-term safety of pravastatin in children undergoing regular triple-drug immunosuppressive therapy after cardiac transplantation. METHODS: Nineteen pediatric cardiac transplant recipients (aged 4.4 to 18.9 years) receiving triple immunosuppression therapy consisting of methylprednisolone (19 patients), cyclosporine (INN, cyclosporin) (17 patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 24 hours. Subsequently, the patients took 10 mg pravastatin orally once daily for 8 weeks. The lipid-lowering effect and the safety of pravastatin therapy were studied. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 122.2 +/- 88.2 ng/mL (range, 11.4-305.0 ng/mL), and the area under the plasma concentration-time curve of pravastatin from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL (range, 30.8-701.6 ng.h/mL). These C(max) and AUC(0-10) values are nearly 10-fold higher than the corresponding values reported in hypercholesterolemic children in the absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/- 0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was 1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to those in the hypercholesterolemic children. By 8 weeks of treatment, the concentration of serum total cholesterol decreased by 13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and triglycerides by 6% (not significant, P =.28); the concentration of high-density lipoprotein cholesterol increased by 7% (not significant, P =.30). No clinically significant increases in serum ALT, creatine kinase, or creatinine levels were observed. CONCLUSIONS: The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.

Administration, Oral↗
PubMed2004

Studies of LDL particle size and susceptibility to oxidation and association with glucose metabolism in children after heart transplantation.

BACKGROUND: Increased concentrations of serum triglyceride and low-density lipoprotein (LDL) cholesterol are common after heart transplantation (HTx). These abnormalities may promote transplant vascular disease and atherosclerosis, especially if LDL is small, dense, and oxidized. There have been no previous studies of LDL particle size and LDL susceptibility to oxidation in children after HTx. METHODS: Twenty-three HTx recipients (aged 3-19 years) who received triple-drug immunosuppression therapy after HTx and 181 controls within the same age range participated in the study. Total, high-density lipoprotein, and LDL-cholesterol concentrations; triglyceride concentration, and glucose and insulin concentrations during oral glucose tolerance tests were determined an average of 3 years after HTx (range, 1-7 years). Moreover, we determined serum lipoprotein (a) concentration, apolipoprotein E phenotype, LDL particle size, and indices of LDL susceptibility to copper-induced oxidation in 12 HTx recipients. RESULTS: We found hypertriglyceridemia in 56.5% and hyperinsulinemia in 30.4% of patients. Triglyceride concentration and body mass index were associated significantly with insulin concentration (p < 0.008 for both). Low-density lipoprotein particle size, LDL susceptibility to in vitro oxidation, and lipoprotein (a) concentrations did not differ significantly between HTx patients and controls. Low-density lipoprotein particle size was associated inversely with cyclosporine through level (Neoral, r = -0.59, p = 0.045), whereas weight-adjusted dosage of cyclosporine correlated positively with longer lag time of LDL oxidation (r = 0.69, p = 0.013). CONCLUSIONS: Hypertriglyceridemia and hyperinsulinemia were common in children receiving triple-drug immunosuppression therapy after HTx. Increased cyclosporine through concentration was associated with small LDL particle size but did not increase LDL susceptibility to oxidation.

Adolescent↗
PubMed2004

Neuroradiologic findings in children with renal transplantation under 5 years of age.

Chronic renal failure (CRF) is known to have adverse effects on the neurodevelopmental outcome of affected children. Some of these effects can be ameliorated by transplantation (TX). The cause and nature of the underlying brain injury is not known. We performed a brain magnetic resonance imaging (MRI) study on a group of children after TX to look for brain abnormalities and, if possible, to draw conclusions about their origin. Thirty-three children who received a renal allograft before 5 yr of age were studied. The most common diagnosis was the congenital nephrotic syndrome of Finnish type (29 patients). The male/female ratio was 22/11, the age range 6-11 yr. Pre-TX CT studies of 26 patients were available for comparison. The patient files were studied for relevant clinical history, including pre- and perinatal events, infections, hypertension, hypertensive crises, hypovolemic states and medical emergencies. These risk factors were correlated with the MRI findings. Eighteen patients (54%) had ischemic lesions in the vascular border zones. Mild lesions were seen in 10 patients, moderate in six and severe in two patients. Other findings were rare, including infarcts in the main vascular territories and basal ganglia, and central and cortical atrophy. The pre-TX CT's revealed border zone infarcts in six patients. Hemodynamic crises were reported in 14 patients and correlated well with border zone infarcts. The age at TX was greater and the duration of dialysis longer in those with border zone infarcts than in those without. Low gestational age, perinatal complications, and septic infections were not statistically significant risk factors. Because of the lack on serial imaging studies we do not know the exact timing of these brain infarcts. The good correlation to pre-TX hemodynamic crises seems, however, to indicate that most of these lesions could be prevented by careful clinical monitoring and early TX.

Adolescent↗
PubMed2004

Psychosocial adjustment and quality of life after renal transplantation in early childhood.

Psychosocial adjustment and quality of life has been reported good in children after a successful renal transplantation (Tx). There are, however, few reports of using standardized methods in evaluating these issues, particularly in small children. We investigated the psychosocial adjustment in 32 children at school age (mean 9.6 +/- 1.6), who had received a renal Tx under the age of 5 yr, using the Achenbach Child Behavior Checklist with data collected from both parents (CBCL) and teachers (CBCL-TRF). Health-related quality of life (HRQOL) was assessed by interviewing the children using a 17-dimensional (17D) health-related measure and compared to HRQOL of 244 normal school children. The effect of additional diseases and comorbidity on psychosocial adjustment and HRQOL was assessed. The total scores on the CBCL did not differ from normative samples of healthy children. However, somatic complaints and social problems were reported more frequently in boys, and attention problems in both boys and girls. Patients with pathological scores had significantly more comorbidity (p = 0.03) and were more often attending a special school (p = 0.007) than patients with normal scores. The global 17D HRQOL index was significantly lower than measured in healthy controls (94 +/- 5 for controls and 85 +/- 7 for patients, p < 0.0001). It is of crucial importance to further minimize the risk factors leading to comorbidity in children after Tx. HRQOL assessment by the children themselves can be used to direct interventions and support the children's psychosocial adjustment.

Age Factors↗
PubMed2004

Podocytes are firmly attached to glomerular basement membrane in kidneys with heavy proteinuria.

Glomerular epithelial cells (podocytes) play an important role in the pathogenesis of proteinuria. Podocyte foot process effacement is characteristic for proteinuric kidneys, and genetic defects in podocyte slit diaphragm proteins may cause nephrotic syndrome. In this work, a systematic electron microscopic analysis was performed of the structural changes of podocytes in two important nephrotic kidney diseases, congenital nephrotic syndrome of the Finnish type and minimal-change nephrotic syndrome (MCNS). The results showed that (1) podocyte foot process effacement was present not only in proteinuric glomeruli but also in nonproteinuric MCNS kidneys; (2) podocytes in proteinuric glomeruli did not show detachment from the basement membrane or cell membrane ruptures; (3) the number of pinocytic membrane invaginations in the basal and apical parts of the podocytes was comparable in proteinuric and control kidneys; (4) in proteinuric kidneys, the podocyte slit pore density was decreased by 69 to 80% and up to half of the slits were so "tight" that no visible space between foot processes was seen; thus, the filtration surface area between podocytes was dramatically reduced; and (5) in the narrow MCNS slit pores, nephrin was located in the apical part of the podocyte foot process, indicating vertical transfer of the slit diaphragm complex in proteinuria. In conclusion, these results suggest that protein leakage in the two nephrotic syndromes studied occurs through defective podocyte slits, and the other structural alterations commonly seen in electron microscopy are secondary to, not a prerequisite for, the development of proteinuria.

Basement Membrane↗
PubMed2004

Nephrin gene (NPHS1) in patients with minimal change nephrotic syndrome (MCNS).

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is a major problem in pediatric nephrology. While the pathogenesis of MCNS is not known, the latest discoveries in the genetic diseases indicate that glomerular epithelial cells (podocytes) and the slit diaphragm play a primary role in development of proteinuria. Because nephrin is known to be a major component of the slit diaphragm, we analyzed the structure of nephrin gene (NPHS1) in patients with MCNS of different severity. METHODS: Clinical data and DNA samples were collected from 25 adults who had biopsy-proven MCNS in childhood. A direct sequencing was performed to all 29 exons of the NPHS1 gene. The significance of the findings was evaluated by similar analysis of DNA samples from 25 healthy control patients. RESULTS: The analysis of NPHS1 revealed no specific MCNS-associated mutation. However, 5 of the 25 MCNS patients had heterozygous allelic variants leading to nonconservative amino acid substitutions not previously reported (G879R; R800C; T294I; A916S). One of the five patients also had the Fin-major mutation, and two had new, conservative amino acid substitutions (S786N; A342G). Three of the five patients were classified as steroid sensitive, one was an early nonresponder, and one patient showed clear resistance to steroid treatment. Six known polymorphic changes in NPHS1 were also found, three of them leading to amino acid changes. The number of allelic variants was high both in MCNS patients and control patients (mean 3.0 and 2.6). CONCLUSION: The results suggest that genetic changes in nephrin may have a pathogenetic role in some patients with MCNS.

Adolescent↗
PubMed2003

Psychosocial adaptation after solid organ transplantation in children.

The possibility of extending life with advanced medical procedures such as organ transplantation in childhood has made it possible to focus on patients' well-being in a wider perspective. They still experience a high prevalence of medical and physical disabilities, which definitively have an impact on a child's psychosocial adjustment after transplantation. Many disabilities originate before transplantation, and much effort should be taken to diminish possible complications and ameliorate growth and neurodevelopment, which have an impact for later adjustment regardless of a successful transplantation. Well-being and QOL are not necessarily always correlated to the degree of physical disability. Different social, financial, and demographic factors also have an impact, as do children's and families' ability to cope with a chronic disorder. Nonadherence and noncompliance are a great problem, particularly in adolescents. They are the result and a possible cause of inferior psychosocial adjustment. Continuous multidisciplinary support, follow-up, and education are needed to cope with this problem. Validated and reliable health status measures in pediatric transplant recipients are scarce in the literature, and few assessments can be completed by the children themselves. A continuing effort must be made to improve psychosocial adjustment and QOL after transplantation to achieve the ultimate goal in medicine: the overall well-being of our patients.

Adaptation, Psychological↗
PubMed2003

Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post-transplantation dosing in pediatric kidney allograft recipients.

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (<2, 2-8 and >8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients <2, 2-8, and >8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients <2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.

Adolescent↗
PubMed2002

Proteinuria and prenatal diagnosis of congenital nephrosis in fetal carriers of nephrin gene mutations.

High concentrations of alpha-fetoprotein (AFP) are used for prenatal diagnosis of the Finnish type of congenital nephrotic syndrome (NPHS1). We investigated the validity of this test. We retrospectively established fetal NPHS1 genotype and assessed renal pathology in 21 pregnancies that had been terminated because of raised concentrations of AFP in amniotic fluid. 12 fetuses were homozygous and nine were heterozygous (carriers) for NPHS1 mutations. Raised concentrations of AFP and similar proteinuric features in fetal kidneys were seen in both groups, indicating that these signs are unreliable for prenatal diagnosis of congenital nephrosis. We strongly recommend the use of mutation analysis of the NPHS1 gene to confirm the AFP results in prenatal diagnosis of NPHS1.

Alleles↗
PubMed2002

The use of fine-needle aspiration biopsy in detection of acute rejection in children after liver transplantation.

Diagnosis of acute rejection after liver transplantation is based mainly on clinical signs and the liver core biopsy findings. In this study we retrospectively analyzed our data on the routine use of fine-needle aspiration biopsy (FNAB) after 63 pediatric liver transplantations. A total of 824 FNABs was taken during the postoperative hospitalization, with a mean of 13 biopsies per patient. Forty-nine acute rejection episodes were diagnosed and treated after 39 transplantations (62%). The FNAB analysis detected rejections often before clinical signs. At the time of rejection diagnosis, fever was present in 38% of the patients, and serum bilirubin and alanine aminotransferase were elevated in only 19% and 13%, respectively. The rejections responded well to oral methylprednisolone, and lymphoglobulins were needed in only two episodes (4%). The results indicate that FNAB is a safe and sensitive method for the diagnosis and follow up of acute cellular rejection in pediatric liver recipients.

Acute Disease↗
PubMed2002

Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin.

BACKGROUND: Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) is caused by mutations in the NPHS1 gene. NPHS1 codes for nephrin, a cell adhesion protein located at the glomerular slit diaphragm. Renal transplantation is the only treatment option for most patients with NPHS1. We have previously described recurrence of severe proteinuria in grafts transplanted to children with NPHS1. Here we studied the pathophysiology of this proteinuria. METHODS: Clinical data, light and electron microscopic findings as well as the expression of nephrin in the proteinuric grafts were studied. The patients' sera were screened for antibodies against kidney glomerulus and nephrin molecule using indirect immunofluorescence and ELISA. RESULTS: Fifteen episodes of recurrent nephrotic syndrome occurred in 13 (25%) of 51 grafts transplanted to 45 Finnish children with NPHS1. All nine patients with recurrence had a Fin-major/Fin-major genotype, which leads to absence of nephrin in the native kidney. Rescue therapy (cyclophosphamide) was successful in seven episodes, but six kidneys were lost due to this process. Antibodies reacting against glomerulus were found in eight, and high anti-nephrin antibody levels were detected in four of the nine patients. In electron microscopy, the fusion of the foot process and decreases in the detectable slit diaphragms in the podocyte pores were observed. The expression of nephrin mRNA was markedly reduced in two, and granular staining for nephrin was seen in three of five grafts. CONCLUSIONS: Circulating anti-nephrin antibodies seem to have a pathogenic role in the development of heavy proteinuria in kidney grafts of NPHS1 patients with Fin-major/Fin-major genotype.

Autoantibodies↗
PubMed2002

SLC26A3 mutations in congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte absorption. It is characterized by persistent secretory diarrhea resulting in polyhydramnios and prematurity prenatally, and dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive immediately after birth. CLD is caused by mutations in the solute carrier family 26, member 3 gene (SLC26A3, alias CLD or DRA), which encodes a Na+-independent Cl-/HCO3- (or OH-) exchanger. SLC26A3 is a member of the SLC26 sulfate permease/anion transporter family and it is expressed mainly in the apical brush border of intestinal epithelium. The only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. A wide variety of different mutations in the SLC26A3 gene have been associated with CLD with no apparent evidence of phenotype-genotype correlation. The clinical course of CLD, however, is variable and may rather depend on environmental factors and compensatory mechanisms than mutations. In this report, we present a summary of all published and two novel SLC26A3 mutations and polymorphisms, and review them in the context of their functional consequences and clinical implications.

Antiporters↗
PubMed2002

Growth after renal transplantation in infancy or early childhood.

Forty-one children <5 years of age at kidney transplantation (TX) were investigated for growth, bone age, and renal function up to 7 years ( n=26) after TX. All children received triple immunosuppression, including alternate-day corticosteroid treatment. Catch-up growth was seen in 81% of 30 children without growth hormone (GH) treatment. Children <2 years of age without GH had a mean height standard deviation score (hSDS) of -1.1+/-0.8 at TX and -1.1+/-0.5 at 7 years; children between 2 and 5 years improved their hSDS from -1.9+/-0.9 to -0.4+/-0.8 ( P<0.0001). The hSDS at TX correlated inversely with the DeltahSDS from TX to 7 years ( r=-0.80, P=0.0002). Glomerular filtrations rate (GFR) at 5 years post TX correlated with the subsequent growth rate from 5 to 7 years TX ( r=0.58, P=0.01). Catch-up growth was seen in all 11 children receiving GH. Their mean hSDS improved from -2.5+/-0.9 to -1.1+/-0.9 ( P<0.0001). In the majority of children receiving a kidney graft in early life, triple immunosuppression with alternate-day steroids can ensure catch-up growth. In children <5 years of age at TX, growth is predicted better by the degree of stunting than by age.

Age Determination by Skeleton↗
PubMed2002

Serum C-reactive protein in pediatric kidney and liver transplant patients.

The clinical manifestations of different complications after organ transplantation (Tx) are often vague, and simple laboratory tests for early diagnosis would be valuable. In this work we retrospectively analyzed our data on the daily measurements of serum C-reactive protein (CRP) in 132 children after 63 liver and 83 kidney Txs. A total of 3,886 CRP measurements were performed and 353 episodes of elevated CRP were recorded. One-third of these were regarded as a response to surgery. The CRP level normalized within 5-10 days post-operatively in patients who had a favorable outcome, but in patients with a poor outcome CRP tended to remain elevated. Half of the CRP elevations were associated with complications such as acute rejection, infection or thrombotic events. An elevated serum CRP level was found in 68% of the rejection episodes, in 88% of the bacterial infections, and in 73% of the viral infections. The most significant elevations were associated with bacterial infection. In nine of 11 vascular complications, an elevation of CRP was also recorded. Serum CRP responded to rejection therapy in 86% of the episodes. The initial CRP level did not predict steroid-resistant rejection. CRP seemed to be a more sensitive marker than fever or white blood cell (WBC) count in all complications. We conclude that the daily measurement of serum CRP is a simple and fairly sensitive, but non-specific, method for detecting rejection and infectious complications after pediatric liver and kidney Tx.

Adolescent↗