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H Jalanko

Publications and source records attributed to H Jalanko.

At least 19 recordsLinked to original sources
PubMed1999

Nephrin is specifically located at the slit diaphragm of glomerular podocytes.

We describe here the size and location of nephrin, the first protein to be identified at the glomerular podocyte slit diaphragm. In Western blots, nephrin antibodies generated against the two terminal extracellular Ig domains of recombinant human nephrin recognized a 180-kDa protein in lysates of human glomeruli and a 150-kDa protein in transfected COS-7 cell lysates. In immunofluorescence, antibodies to this transmembrane protein revealed reactivity in the glomerular basement membrane region, whereas the podocyte cell bodies remained negative. In immunogold-stained thin sections, nephrin label was found at the slit between podocyte foot processes. The congenital nephrotic syndrome of the Finnish type (NPHS1), a disease in which the nephrin gene is mutated, is characterized by massive proteinuria already in utero and lack of slit diaphragm and foot processes. These features, together with the now demonstrated localization of nephrin to the slit diaphragm area, suggests an essential role for this protein in the normal glomerular filtration barrier. A zipper-like model for nephrin assembly in the slit diaphragm is discussed, based on the present and previous data.

Cell Membrane↗
PubMed1999

Successful liver transplantation after induction chemotherapy in children with inoperable, multifocal primary hepatic malignancy.

BACKGROUND: The prognosis for primary epithelial liver tumor in children in whom radical surgery cannot be performed after chemotherapy is poor. Orthotopic liver transplantation has resulted in mortality up to 50%, largely as a result of problems in determining the criteria for transplantation. METHODS: We report results on liver transplantation for primary epithelial liver malignancy in five children (mean age at transplantation: 6.0 years). Only patients with inoperable residual tumor in the liver after four cycles of multidrug chemotherapy, but without extrahepatic infiltration or metastases, were considered eligible for transplantation. RESULTS: Mean follow-up was 4.6 years. Patient and graft survival was 100%, with no signs of residual or de novo malignancy. CONCLUSION: In children with inoperable primary liver malignancy with no extrahepatic tumor growth, orthotopic liver transplantation has an excellent outcome.

Adolescent↗
PubMed1999

Graft function 5-7 years after renal transplantation in early childhood.

BACKGROUND: Low recipient age is still a risk factor for graft failure after kidney transplantation (Tx). Detailed prospective reports on long-term graft function in small children after renal Tx are still lacking. METHODS: Forty-nine kidney allograft recipients who received transplants before the age of 5 years were followed prospectively. The most common disease was congenital nephrotic syndrome of the Finnish type. Twenty patients were recipients of living related donors (LRD), and 29 were cadaveric kidney (CAD) recipients. All patients received triple immunosuppression. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), sodium, urate, and potassium handling, and concentrating capacity were studied for up to 7 years after Tx. RESULTS: Patient survival 7 years after Tx was 100% for LRD and 96% for CAD recipients. Graft survival was 94% for LRD and 79% for CAD recipients (P=NS) and 89% and 83% for children >2 years and <2 years of age at Tx, respectively (P=NS). Five years after Tx, GFR was 70 vs. 64 and ERPF was 380 vs. 310 ml/min/1.73 m2 for LRD and CAD recipients, respectively (P=NS). Mean absolute GFR remained stable. GFR was lower in children who received transplants at <2 years than in children who received transplants at >2 years of age, 54 vs. 75 ml/min/1.73 m2 (P=0.02). Sodium handling remained intact, but hyperuricemia was seen in 43-67%; 17-33% showed abnormal handling of potassium; and most patients had a subnormal concentrating capacity. CONCLUSIONS: Excellent long-term graft survival and good graft function can be achieved with triple immunosuppression, even in young CAD kidney recipients.

Cadaver↗
PubMed1998

Long-term follow up of renal function and histology after renal allograft transplantation in early childhood.

Survival rates, renal function, and histopathology were evaluated in 49 prospectively followed patients transplanted under 5 years of age at our center. Most patients (84%) suffered from congenital nephrosis of the Finnish type. Triple immunosuppression with cyclosporine administered in three daily doses to pre-school children was used. Patient survival 7 years after transplantation was 98% and graft survival 88%. All graft losses were due to post-transplantation nephrosis. The proportion of pathological findings in the follow-up biopsies did not change substantially with time. Five years after transplantation, 47% showed a normal histology and after 7 years this rose to 67%. Mean glomerular filtration rate (GFR) was 68 and 55 ml min per 1.73 m2 5 years and 7 years, respectively, after transplantation. The decline in GFR with time was significant. We conclude that good long-term results can be achieved with individually tailored triple immunosuppression in the youngest age group, even with cadaveric donors.

Child, Preschool↗
PubMed1998

Paediatric kidney transplantation.

Renal transplantation is the optimal form of renal replacement therapy leading to substantial improvement in the quality of life. It has rapidly become the standard treatment for end-stage renal disease in children. However, despite impressive short-term results significant long-term problems remain unsolved. Because of the lack of effective treatment for chronic rejection and common recipient noncompliance, allograft half-life has not improved significantly during the last decade. A paediatric recipient is likely to need several retransplantations in adulthood. Moreover, the immunosuppressive drugs used today have potentially serious side-effects including nephrotoxicity and de novo malignancy. These are especially relevant for paediatric recipients who will continue to receive therapy for several decades. Most therapeutic protocols used for children are derived from those used for adults. However, the metabolic differences between an adult and a growing and developing paediatric transplant recipient are not always adequately appreciated before these new therapies are initiated. In the near future, we are likely to see new and more efficient drugs become available. It is important that we try to understand their properties in children and use them and our current arsenal on an individual basis aiming at optimal graft survival but also at avoiding unnecessary adverse effects.

Adolescent↗
PubMed1997

Kidney function after 1:1 conversion to the cyclosporine microemulsion formulation in children with liver allografts.

BACKGROUND: One-to-one (mg:mg) conversion from the conventional to the microemulsion formulation of cyclosporine (CsA) is advocated as a simple way to use the new therapeutic regimen. However, the potentially harmful effects of the conversion on kidney function in nonrenal transplant recipients are poorly known. METHODS: Renal effects of the conversion were prospectively investigated in 22 pediatric liver transplant recipients (mean age, 8.4 years; mean time from transplantation, 3.2 years). Patients were followed for 12 months. Pharmacokinetic studies were performed at baseline and 5 days and 6 and 12 months after conversion. RESULTS: Peak concentration, minimum concentration, average steady state concentration, and area under the concentration-versus-time curve increased by 60-130% after conversion. Graft losses, progressive deterioration of graft function, and acute rejection episodes did not occur. The mean glomerular filtration rate (GFR) was 103 ml/min/1.73 m2 at baseline and 100 ml/min/1.73 m2 after 12 months. However, 6 of the 22 patients showed at least a 15% (range, 16-38%) decrease in GFR between baseline and 6 months (P<0.01). They had a significantly higher increase in average steady state concentration between baseline and 6 months than the six patients with the best outcome in GFR during the same time period (164 ng/ml vs. 53 ng/ml, P<0.05). At this point (6 months), target CsA trough levels were reduced by 20-30%, while the mean area under the concentration-versus-time curve remained above that obtained at baseline. The GFR of three of the six patients subsequently improved. CONCLUSIONS: One-to-one conversion can be performed safely in liver transplant recipients if strict follow-up is feasible.

Adolescent↗
PubMed1997

Infections in infants with congenital nephrosis of the Finnish type.

The incidence and type of infections were retrospectively analyzed in 21 infants with congenital nephrosis of the Finnish type (CNF). During the median follow-up time of 1.1 years the infants suffered from 63 verified and 62 suspected episodes of sepsis. These accounted for half of all infections recorded. Forty percent of bacteremias were caused by coagulase-negative staphylococci, 16% were caused by Staphylococcus aureus, 17% were streptococcal, and 24% were caused by Gram-negative bacteria. One infant died of pleural empyema, but otherwise the outcome of infections was good. The use of central venous lines tended to increase the rate of staphylococcal bacteremias but had no significant effect on the overall incidence of infections. Prophylactic use of antibiotics did not reduce the incidence of septic or other infections. Infants with CNF had low levels of serum IgG, but prophylactic immunoglobulin infusions (0.5-1.0 g once or twice a week) did not reduce the frequency of infections, probably because the infused IgG was quickly lost into the urine. The results indicate that infants with CNF often suffer from septic infections associated with the invasive treatment modalities. Parenteral antibiotics covering the hospital strains of bacteria (especially staphylococci) should be started without delay when a nephrotic patient is not doing well.

Anti-Bacterial Agents↗
PubMed1997

Persistent cytomegalovirus in liver allografts with chronic rejection.

Cytomegalovirus (CMV) infection is one of the suggested risk factors for chronic allograft rejection. Clinical and experimental studies have shown that CMV is somehow implicated in rejection mechanisms and in the generation of graft arteriosclerosis, characteristic of chronic rejection. In liver transplantation, there is also evidence of an association between CMV and vanishing bile duct-syndrome (VBDS), which is characteristic of chronic liver allograft rejection. In this study, the role of posttransplant CMV infection and of acute rejection in the patients with irreversible, histologically confirmed chronic liver rejection with VBDS and vasculopathy was analyzed. Ten of 200 (5%) consecutive liver transplants were lost due to chronic rejection, from between 5 and 28 months from transplantation. In these 10 patients, acute rejections were frequent, and nine of ten patients had at least one episode of rejection early after transplantation. All patients (10 of 10) had a history of CMV infection usually following acute rejection. To investigate the role of CMV in chronic rejection, nine available removed grafts were examined for the presence of the CMV genome by DNA-hybridization in situ using a biotinylated CMV-DNA probe. Persistent CMV-DNA was found in all of those available grafts with chronic rejection. CMV-DNA was strongly expressed in the remaining bile ducts and moderately expressed in the endothelial cells of the vascular structures, the CMV positivity of hepatocytes varied from graft to graft. Thus, persistent CMV genome was found in those structures that are the major targets of the chronic rejection process in the liver. These findings support the previous suggestion of an association between CMV and chronic allograft rejection.

Bile Ducts↗
PubMed1997

Kidney function in cyclosporine-treated pediatric heart transplant recipients.

BACKGROUND: End-stage kidney disease may develop in 1% to 3% of cyclosporine-treated heart transplant recipients, and most patients show a decreased glomerular filtration rate. There are little data on kidney function in pediatric recipients, although good function is needed for their optimal development. METHODS: Kidney function was prospectively investigated in 10 children receiving triple immunosuppression (cyclosporine, azathioprine, methylprednisolone) during the first 18 months after heart transplantation. The early cyclosporine trough level target was 300 to 500 micrograms/L and 100 to 200 micrograms/L after the first year. 51Chromium-ethylenediamine tetraacetic acid, para-amino hippuric acid, lithium, and sodium clearances, measurements of serum and urinary electrolytes, and urinary concentration tests were performed. Renal biopsy specimens were obtained from four patients after 18 months. RESULTS: Heart function was good in all patients. Six patients (60%) remained rejection-free at 18 months. The mean glomerular filtration rate was 92.4 ml/min/1.73 m2 before transplantation, increased to 115 by 6 months (p < 0.05), and thereafter remained stable. The mean renal plasma flow was 487 ml/min/1.73 m2 after 18 months. Hypertension was seen in all patients at discharge but in only one at 18 months. Mild hyperuricemia was the most common sign of tubular dysfunction occurring in five patients at discharge but in only two patients at 18 months. The result of kidney histopathologic study was normal in three of four patients, and cyclosporine nephrotoxicity was not diagnosed. CONCLUSIONS: Triple immunosuppression with cyclosporine adequately protects the graft against acute rejection. It is compatible with normal glomerular function and leads to only minor tubular disturbances.

Adolescent↗
PubMed1996

Comparison of conventional oral cyclosporine and cyclosporine microemulsion formulations in children with a liver transplant.

We studied 22 children (mean age: 8.42 years, range: 1.9-15.6 years) with a liver transplant to compare the pharmacokinetics of oral cyclosporine (CsA) microemulsion to the conventional formulation. The CsA treatment (mean dose: 5.9 mg/kg/day, range: 3.0-11.7 mg/kg/day) was converted 1:1 on a milligram-to-milligram basis to the microemulsion formulation. Five days after the conversion, the mean peak blood CsA concentration was higher (microemulsion: 963 ng/ml, range: 518-1864 ng/ml; conventional: 431 ng/ml, range: 98-888 ng/ml; P<0.0001) and it was reached faster (median time of peak concentration: 1.6 hr vs. 2.9 hr, range: 1.0-3.0 hr vs. 1.9-4.0 hr; P=0.0009). The absorption lasted on the average 19% longer after the conventional formulation. The area under the concentration versus time curve (AUC) was larger after the microemulsion formulation in all but one patient (P=0.001) by a mean factor of 1.80 (range: 0.72-3.04). The trough CsA level after the microemulsion formulation was more closely related to peak concentration (r2=0.86 vs. 0.45) and AUC (r2=0.84 vs. 0.47); thus, therapeutic drug monitoring may be more useful. After 6 months on the new formulation, the results for the whole group were similar, but in five children the AUC was comparable to the AUC obtained with the conventional formulation. No rejections occurred, and the liver and kidney functions remained unchanged. A 1:1 conversion can be safely performed in children, based on a 6-month follow-up. However, the total drug exposure changes in significant ways, which, on a long-term basis, may improve the immunosuppression in an underimmunosuppressed patient, but may increase the risk for dose-related adverse effects in others.

Administration, Oral↗
PubMed1996

Recombinant human growth hormone treatment. Its effect on renal allograft function and histology.

Our objective was to investigate the effects of recombinant human growth hormone (rhGH) treatment on long-term renal allograft function and histopathology. RhGH is a potent therapy for poor growth after renal transplantation. However, rhGH has proinflammatory properties and may induce acute rejection or accelerate chronic rejection. Nine prepubertal rhGH-treated renal transplanted children and nine pair-matched controls were studied 18 (before the start of rhGH) and 36 months after transplantation (mean duration of rhGH-treatment 14 months). 51Cr-EDTA- and PAH-clearances were performed. A protocol renal biopsy was done at 36 months. Growth showed significant improvement during rhGH (P<0.01). One graft loss occurred in both groups. One acute rejection was seen in the control group. There was no difference in the rate pf change in 51Cr-EDTA-or PAH-clearance between the two groups. Histopathological findings were mostly mild. One new onset chronic rejection developed in both groups. Proximal tubular atrophy was more extensive in the rhGH-treated patients (P<0.05), but there was no uniform trend toward more severe findings. RhGH improved growth, and no significant differences were seen in allograft function or histopathology; however, larger trials controlled for pretreatment renal function and immunosuppression are needed.

Acute Disease↗
PubMed1996

Distribution of renal integrin receptors and their ligands in congenital nephrotic syndrome of the Finnish type.

The aim of this study was to examine the distribution of beta 1 and alpha v integrins (Ints) and some of their ligands in the kidneys of patients with congenital nephrotic syndrome of the Finnish type (CNF) and in controls using indirect immunofluorescence with monoclonal antibodies. The mesangial reactivity of Int alpha 1 and Int beta 1 subunits was more variable and an increased glomerular reactivity with Int alpha 3 and Int-alpha 6 antibodies was found in CNF kidneys than in controls. Int alpha 2 subunit was either completely missing from or found in significantly lesser amounts in CNF kidney glomeruli. The immunoreactivity for Int alpha v was more variable, fainter and also more granular in CNF samples than in control kidneys. The glomerular reactivity for Int beta 5 was more diffuse and weaker, and in sclerotic Bowman's capsules more intense in CNF kidneys than in controls. Immunoreactivity for Int beta 6 was restricted and was comparable in extent in CNF and control kidneys. Of the extracellular matrix components studied, the expression of EDAFn, EDBFn, OncFn, Ln alpha 2 chain, Ln beta 1 chain and tenascin was increased. This is also seen in several glomerular diseases with inflammation and sclerosis. Immunoreactivity for vitronectin was decreased. Several differences were found in the intensity or location of the immunostaining for the beta 1 and alpha v Ints and their ligands in CNF kidneys compared with controls, which have not been found in any other proteinuric disease. Disturbed Int expression pattern in CNF may specifically reflect the disturbance of glomerular function caused by the primary defect in this disease.

Antibodies, Monoclonal↗
PubMed1996

Sphingolipid activator proteins in a human hereditary renal disease with deposition of disialogangliosides.

Congenital nephrotic syndrome of the Finnish type is a recessively inherited renal disease with glomerular deposits of the disialoganglioside O-acetyl-GD3. Sphingolipid activator proteins (saposins) stimulate the degradation of glycosphingolipids by lysosomal enzymes, and defects in saposins cause accumulation of substrate lipids in the affected tissues in lysosomal storage disease. Here we report a study of the role of saposins in the accumulation of O-acetyl-GD3 in kidneys of congenital nephrotic syndrome patients. At the mRNA level, the expression of saposin precursor in diseased kidneys appeared normal, and the nucleotide sequence analysis of cDNA clones did not reveal abnormalities in the prosaposin gene. Immunohistologically, saposins were localized mainly to the epithelial cells of the distal renal tubules or to the parietal epithelial cells of glomeruli. In the nephrotic syndrome kidneys, the staining pattern was highly granular and appeared mostly in the apical part of the epithelial lining, unlike the control kidneys. These results show that a major site of ganglioside metabolism is located in the distal nephron. Furthermore, these results suggest that saposins are not directly involved in the metabolism of the terminal sialic acids of disialogangliosides in the nephrotic syndrome kidneys.

Adult↗
PubMed1996

Mechanisms of proteinuria: vascular permeability factor in congenital nephrotic syndrome of the Finnish type.

Vascular permeability factor (VPF) is the most potent known mediator of vessel wall permeability. In the kidney, it is expressed preferentially in the glomerular visceral epithelial cells. The present study was designed to clarify the proposed role of VPF in diseases with increased glomerular permeability as here exemplified by the congenital nephrotic syndrome of the Finnish type (CNF). For this, we studied the expression levels and the sites of synthesis of VPF and its kinase-insert domain receptor (KDR) in kidneys of patients with CNF using Northern and in situ hybridization techniques and immunohistologic staining with anti-VPF antibody. In addition, we extended the study to include analysis of fetal kidney tissue and cultured glomerular cells of normal and CNF kidneys. In CNF and in normal kidneys VPF was localized in the visceral epithelial aspect of the glomeruli and in the collecting ducts, as also earlier described. A new finding was its localization also in the juxtaglomerular area. The VPF receptor KDR was found in glomeruli in the endothelial cells, but it was not detected in the peritubular capillaries. no consistent differences in the levels of VPF or KDR mRNAs or in their sites of production were seen in CNF and control samples. Also the distribution of VPF antigen in the CNF kidneys and normal kidneys was similar. Thus, we propose that VPF and KDR are not directly involved in the pathogenesis of the proteinuria in CNF.

Cells, Cultured↗