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Biomedical subjects

Hannu Jalanko

Publications and source records attributed to Hannu Jalanko.

At least 19 recordsLinked to original sources
PubMed2005

Clinical features and outcome of childhood minimal change nephrotic syndrome: is genetics involved?

The pathogenesis of minimal change nephrotic syndrome (MCNS) is still unknown. We performed a clinical and genetic evaluation of 104 adults (mean age 35 years) who presented with MCNS in childhood (mean follow-up 30 years). Clinical data and the present health status were evaluated. Also, the genes encoding the four major slit diaphragm proteins, nephrin, podocin, Neph1 and CD2-associated protein were sequenced in 38 patients with MCNS of varying severity. MCNS presented at the mean age of 5 years, and 80% of the patients relapsed 1-28 (median 3) times during childhood. The 14 subjects (14%) who had proteinuric episodes still in adulthood had a refractory disease already as children. The participants did not show a strong tendency for allergy or immune diseases, and no familial clustering of MCNS was observed. The genetic analyses revealed heterozygous amino acid changes in nephrin and podocin in 10 of the 38 patients studied. On the other hand, the genes coding for Neph1 and CD2AP were highly conserved and no amino acid substitutions were detected. In conclusion, MCNS is a multifactorial disease, in which genetics play a minor role. Allelic variants of the podocyte proteins may, however, modify the phenotype in occasional individuals.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Recombinant human growth hormone treatment after liver transplantation in childhood: the 5-year outcome.

BACKGROUND: Because the results of short-term recombinant human growth hormone (rhGH) treatment in children with growth impairment after liver transplantation (LTx) have been promising, we have studied the long-term effects of rhGH on growth and graft function after LTx. METHODS: Indications for rhGH treatment were height standard deviation score (hSDS) below -2.0 or growth velocity SDS below 0 and LTx at least 18 months before inclusion. Eight growth-retarded children were treated with rhGH for more than 5 years. RESULTS: During the first year, median growth rate improved from 3.3 to 7.0 cm/year. In the second and third year, growth velocity remained high at 6.6 cm/year and 6.2 cm/year, respectively (P=0.008). In the fourth year, median growth velocity started to decline but still remained above baseline during the fifth year of treatment (4.2 cm/year). The median hSDS improved from -3.6 to -2.7. During the rhGH treatment, no acute rejection episodes were detected, and graft function remained stable in all except one patient. She was diagnosed with chronic rejection in the third year of rhGH treatment. The patient had elevated liver enzymes and abnormal liver function tests already before rhGH treatment. CONCLUSIONS: The efficacy of rhGH treatment is sustained after the first year in liver-transplant children with non-GH-deficient growth retardation. Because of a potential risk of side effects, close monitoring of these patients is required.

Child↗
PubMed2005

Kidneys with heavy proteinuria show fibrosis, inflammation, and oxidative stress, but no tubular phenotypic change.

BACKGROUND: Sustained proteinuria is a major factor leading to kidney fibrosis and end-stage renal failure. Tubular epithelial cells are believed to play a crucial role in this process by producing mediators leading to fibrosis and inflammation. Congenital nephrotic syndrome of the Finnish type (NPHS1) is a genetic disease caused by mutations in a podocyte protein nephrin, which leads to constant heavy proteinuria from birth. In this work we studied the tubulointerstitial changes that occur in NPHS1 kidneys during infancy. METHODS: The pathologic lesions and expression of profibrotic and proinflammatory factors in nephrectomized NPHS1 kidneys were studied by immunohistochemistry, Western blotting, and cytokine antibody array. Oxidative stress in kidneys was assessed by measurement of gluthatione redox state. RESULTS: The results indicated that (1) severe tubulointerstitial lesions developed in NPHS1 kidneys during infancy; (2) tubular epithelial cells did not show transition into myofibroblasts as studied by the expression of vimentin, alpha-smooth muscle actin (alpha-SMA), collagen, and matrix metalloproteinases 2 and 9 (MMP-2 and -9); (3) the most abundant chemokines in NPHS1 tissue were neutrophil activating protein-2 (NAP-2), macrophage inhibiting factor (MIF), and monocyte chemoattractant protein-1 (MCP-1); (4) monocyte/macrophage cells expressing CD14 antigen were the major inflammatory cells invading the interstitium; (5) the arteries and arterioles showed intimal hypertrophy, but the microvasculature in NPHS1 kidneys remained quite normal; and (6) excessive oxidative stress was evident in NPHS1 kidneys. CONCLUSION: Heavy proteinuria in NPHS1 kidneys was associated with interstitial fibrosis, inflammation, and oxidative stress. The tubular epithelial cells, however, were resistant to proteinuria and did not show epithelial-mesenchymal transition.

Capillaries↗
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

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↗
PubMed2004

Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.

Nephrin is a key functional component of the slit diaphragm, the structurally unresolved molecular filter in renal glomerular capillaries. Abnormal nephrin or its absence results in severe proteinuria and loss of the slit diaphragm. The diaphragm is a thin extracellular membrane spanning the approximately 40-nm-wide filtration slit between podocyte foot processes covering the capillary surface. Using electron tomography, we show that the slit diaphragm comprises a network of winding molecular strands with pores the same size as or smaller than albumin molecules, as demonstrated in humans, rats, and mice. In the network, which is occasionally stratified, immunogold-nephrin antibodies labeled individually detectable globular cross strands, about 35 nm in length, lining the lateral elongated pores. The cross strands, emanating from both sides of the slit, contacted at the slit center but had free distal endings. Shorter strands associated with the cross strands were observed at their base. Immunolabeling of recombinant nephrin molecules on transfected cells and in vitrified solution corroborated the findings in kidney. Nephrin-deficient proteinuric patients with Finnish-type congenital nephrosis and nephrin-knockout mice had only narrow filtration slits that lacked the slit diaphragm network and the 35-nm-long strands but contained shorter molecular structures. The results suggest the direct involvement of nephrin molecules in constituting the macromolecule-retaining slit diaphragm and its pores.

Animals↗
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↗