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Congenital nephrotic syndrome (CNS) was primarily considered one disease entity. Hence, one treatment protocol was proposed in the beginning to all CNS patients. Today, with the help of gene diagnostics, we know that CNS is a heterogeneous group of disorders and therefore, different treatment protocols are needed. The most important gene defects causing CNS areNPHS1,NPHS2,WT1,LAMB2, andPLCE1. Before active treatment, all infants with CNS died. It was stated already in the mid-1980s that intensive medical therapy followed by kidney transplantation (KTx) should be the choice of treatment for infants with severe CNS. In Finland, early aggressive treatment protocol was adopted from the USA and further developed for treatment of children with the Finnish type of CNS. The aim of this review is to state reasons for “early aggressive treatment” including daily albumin infusions, intensified nutrition, and timely bilateral nephrectomy followed by KTx at the age of 1–2 years.

Background Mulibrey nanism (MUL) is a rare inherited disease caused by genetic defects affecting peroxisomal TRIM37 protein. MUL affects multiple organs, leading to growth retardation and early onset type 2 diabetes. We aimed to characterize the structure and function of kidneys and the urinary tract in a large cohort of Finnish MUL patients. Methods Ultrasound, magnetic resonance imaging (MRI), and autopsy findings of the kidneys and urinary tract from 101 MUL patients were retrospectively analyzed. Renal function was examined using blood and urine biochemistry. Kidney pathology was assessed by histology and immunohistochemistry from biopsy and autopsy samples. Results Structural anomalies of the kidneys and urinary tract were found in 13 % of MUL patients and renal tumors and macroscopic cystic lesions in 14 % and 43 % respectively. Overall, kidney histology was well preserved, but glomerular cysts with a wide Bowman's space were observed in most samples (87 %). Also, prominent and abundant blood vessels with thick walls were typically seen. Expression of endothelial cell markers and angiogenic growth factors PDGF-B and FGF1 (but not VEGF-A) was significantly increased in MUL kidneys. Markers of fibrosis and epithelial-mesenchymal transformation, a-SMA, and vimentin were moderately up-regulated. Despite radiological and histological changes, most MUL patients (age 0.2-51 years) had normal kidney function. However, 9 out of 36 patients (25 %) had hypertension and 6 out of 26 (23 %) had mildly decreased glomerular filtration. Conclusions Genetic defects in the TRIM37 gene lead to an increased risk for kidney anomalies, renal tumors, and solitary cysts in addition to glomerular cystic lesions, but not to progressive deterioration of renal function.

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p

Renal transplantation (RTx) has become an accepted mode of therapy in infants with severe renal failure. The major indications are structural abnormalities of the urinary tract, congenital nephrotic syndrome, polycystic diseases, and neonatal kidney injury. Assessment of these infants needs expertise and time as well as active treatment before RTx to ensure optimal growth and development, and to avoid complications that could lead to permanent neurological defects. RTx can be performed already in infants weighing around 5 kg, but most operations occur in infants with a weight of 10 kg or more. Perioperative management focuses on adequate perfusion of the allograft and avoidance of thrombotic and other surgical complications. Important long-term issues include rejections, infections, graft function, growth, bone health, metabolic problems, neurocognitive development, adherence to medication, pubertal maturation, and quality of life. The overall outcome of infant RTx has dramatically improved, with long-term patient and graft survivals of over 90 and 80 %, respectively.

Organ transplantation may lead to secondary osteoporosis in children. This study characterized bone histomorphometric findings in pediatric solid organ transplant recipients who were assessed for suspected secondary osteoporosis. Iliac crest biopsies were obtained from 19 children (7.6–18.8 years, 11 male) who had undergone kidney (n = 6), liver (n = 9), or heart (n = 4) transplantation a median 4.6 years (range 0.6–16.3 years) earlier. All patients had received oral glucocorticoids at the time of the biopsy. Of the 19 patients, 21 % had sustained peripheral fractures and 58 % vertebral compression fractures. Nine children (47 %) had a lumbar spine BMD Z-score below −2.0. Histomorphometric analyses showed low trabecular bone volume (< −1.0 SD) in 6 children (32 %) and decreased trabecular thickness in 14 children (74 %). Seven children (37 %) had high bone turnover at biopsy, and low turnover was found in 6 children (32 %), 1 of whom had adynamic bone disease. There was a great heterogeneity in the histological findings in different transplant groups, and the results were unpredictable using non-invasive methods. The observed changes in bone quality (i.e. abnormal turnover rate, thin trabeculae) rather than the actual loss of trabecular bone, might explain the increased fracture risk in pediatric solid organ transplant recipients.

The presence of circulating donor-specific human leukocyte antigen antibodies (HLA-DSA) has been associated with chronic antibody-mediated rejection, leading to progressive graft dysfunction and poor graft survival. The aim of this study was to investigate the incidence and significance of HLA-DSA in paediatric renal transplantation (RTx) patients. A total of 294 post-transplant serum samples from 123 RTx patients were retrospectively analysed for HLA antibodies. Positive samples were further tested for HLA-DSA by a Luminex Single Antigen bead assay. The antibody findings were correlated to measured glomerular filtration rate (GFR) and clinical outcome. HLA antibodies were detected in half of the routine samples (140/294) taken 1 month to 10 years after RTx, and 40% (62/140) of these were HLA-DSA. Overall, one-third (42/123) of the patients had HLA-DSA, which mostly (65%) reacted against class II antigens. Detection of HLA-DSA was not associated with poor GFR at the time of sampling, and no exceptional deterioration of GFR after the HLA-DSA detection was noted in individual patients regardless of the antibody level. The presence of HLA-DSA in the first 2 years posttransplantation was not associated with poorer graft function later on. Detection of HLA antibodies is common in children after RTx, and this finding, as such, does not predict any deterioration of graft function.

Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of cases are caused by genetic defects in the components of the glomerular filtration barrier, especially nephrin and podocin. CNS may also be a part of a more generalized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the genetic forms of CNS, and kidney transplantation is the only curative therapy. Before the operation, management of these infants largely depends on the magnitude of proteinuria. In severe cases, daily albumin infusions are required to prevent life-threatening edema. The therapy also includes hypercaloric diet, thyroxin and mineral substitution, prevention of thrombotic episodes, and prompt management of infectious complications. The outcome of CNS patients without major extrarenal manifestations is comparable with other patient groups after kidney transplantation.

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.

Forty-one children5 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. Children2 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 ( P0.0001). 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 ( P0.0001). In the majority of children receiving a kidney graft in early life, triple immunosuppression with alternate-day steroids can ensure catch-up growth. In children5 years of age at TX, growth is predicted better by the degree of stunting than by age.

Clinical outcome under adequacy control was studied in 10 pediatric patients under 5 years and 11 patients over 5 years of age on continuous peritoneal dialysis (PD). Outcome was compared between the age groups and with our previous results in patients under 5 years of age. Peritoneal equilibration test and 24-h dialysate collection were performed. Laboratory data, clinical status, and diet were recorded. PD prescription was adjusted for these parameters. The mean weekly urea Kt/V was similar and stable in the two age groups (3.1+/-0.6 vs. 3.2+/-0.4 at baseline). The mean weekly creatinine clearance (C(Cr)) was at baseline significantly lower in the younger age group (58.7+/-11.9 vs. 78.0+/-14.9 l/week per 1.73 m2, P=0.004), but later similar. Urea Kt/V and C(Cr) correlated significantly. Hematological and biochemical parameters were stable, and catch-up growth was observed in 62% of the patients during 9 months of follow-up. The outcome for children under and over 5 years of age did not differ significantly. The clinical outcome in patients under 5 years of age improved under adequacy control, when compared with our previous results in patients of the same age. This suggests a positive effect of adequacy control on clinical outcome.

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.

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessively inherited disease characterised by intrauterine onset of massive urinary loss of proteins, 90% of which is albumin. The CNF gene has been localised to the long arm of chromosome 19, but the pathogenesis remains unclear. Historically, all CNF patients died, usually within the first 6 months of life. Today, a normal life can be achieved for a child with CNF by correcting the protein deficiency and normalising nutrition. This is accomplished by early intravenous albumin supplementation, nutritional support, aggressive treatment of complications and early renal transplantation, after bilateral nephrectomy and peritoneal dialysis. In the present article current treatment strategies are reviewed, and our own experience with 43 CNF patients during the last 10 years is presented.