Mechanism of cystogenesis in nephrotic kidneys: a histopathological study.

BACKGROUND: Nephrotic syndrome (NS) is pathological condition characterized by heavy proteinuria. Our study investigates hypothesis that change in cell proliferation of proximal tubules influences primary cilia structure and function and promotes cystogenesis in congenital nephrotic syndrome of the Finnish type (CNF) and focal segmental glomerulosclerosis (FSGS). METHODS: CNF kidneys were analyzed genetically. Proliferation (Ki-67), apoptosis (caspase-3), and primary cilia (α-tubulin) length and structure were analyzed immunohistochemically and ultrastructurally in healthy, CNF and FSGS kidneys. Cyst diameters were measured and correlated with proliferation index. RESULTS: Proximal tubules cells of healthy kidneys did not proliferate. In nephrotic kidneys, tubules with apparently normal diameter covered by cuboidal/columnar epithelium (PTNC) contained 81.54% of proliferating cells in CNF and 36.18% in FSGS, while cysts covered with columnar epithelium (CC) contained 37.52% of proliferating cells in CNF and 45.23% in FSGS. The largest cysts, covered with squamous epithelium (CS) had 11.54% of proliferating cells in CNF and 13.76% in FSGS. Increase in cysts diameter correlated with changes in proliferation index, tubular cells shape, primary cilia formation and appearance of apoptotic cells. CONCLUSIONS: We present a novel histopathological data on the structure and possible changes in function of tubular cell in NS kidneys during cystogenesis. We suggest existence of common principles of cystogenesis in CNF and FSGS kidneys, including serious disturbances of tubular cells proliferation and apoptosis, and faulty primary cilia signaling leading to deterioration of proteinuria in NS kidneys.

Impact of graft loss among kidney diseases with a high risk of post-transplant recurrence in the paediatric population.

BACKGROUND: Some kidney diseases tend to recur in the renal allograft after transplantation. We studied the risk of graft loss among primary renal diseases known for their high risk of recurrence and compared it with that of patients with hypoplasia and/or dysplasia. METHODS: Within the European Society of Paediatric Nephrology and European Renal Association and European Dialysis and Transplant Association (ESPN/ERA-EDTA) registry, we studied children from 33 countries who received a kidney transplant before the age of 20 between 1990 and 2009. Patients were censored after 5 years of follow-up and cumulative incidence competing risk analysis was used to calculate survival curves. RESULTS: Patients with focal and segmental glomerulosclerosis (FSGS), haemolytic uraemic syndrome (HUS), membranoproliferative glomerulonephritis Type I or II (MPGN), IgA nephropathy or Henoch Schönlein Purpura (HSP/IgA) or systemic lupus erythomatosus (SLE) underwent pre-emptive transplantation significantly less often than patients with hypoplasia and/or dysplasia. The rate of living donation was lower among patients with FSGS and SLE than in patients with hypoplasia and/or dysplasia. In comparison with hypoplasia and/or dysplasia patients with a risk of 14.4%, the 5-year risk of graft loss was significantly increased in patients with FSGS (25.7%) and MPGN (32.4%) while it was not significantly increased in children with HUS (18.9%), HSP/IgA (16.3%) or SLE (20.3%). One-year graft survival strongly improved among HUS patients from 17.1% in 1995-1999 to 3.6% in 2005-2009 and was not accompanied by a decrease in the number of transplantations. CONCLUSION: The risk of graft loss is increased among specific causes of renal failure with a high risk of post-transplant recurrence. It seems likely that, due to anticipation of such risk, physicians perform less pre-emptive transplantation and provide fewer grafts from living related donors in patients with these conditions. Improved risk stratification by physicians, resulting in the identification of patients with HUS at higher or lower risk of recurrence, might explain the much improved graft survival rates.

Treatment of steroid unresponsive relapse with plasma exchange in aggressive multiple sclerosis.

The options for treating steroid unresponsive relapses in relapsing remitting multiple sclerosis (RRMS) are modest. We present a small series of patients with an aggressive course of RRMS whose steroid unresponsive relapses were treated with plasma exchange. In the period from January 2007 until February 2009 we identified four patients with steroid unresponsive relapses. All recorded relapses were treated with methylprednisolone, either with 500 mg for 5 days or 1000 mg for 3 days. If there was no improvement, patients were given five cycles of plasma exchange. If there was no recovery after the initial five cycles, five more were administered. Each patient's clinical status was monitored using the extended disability status scale. The median time from symptom onset until starting plasma exchange was 30 days (23-45 days). For four relapses, five cycles of plasma exchange were given with marked recovery in one, moderate in two, and mild in one case. In one patient, after five cycles there was no recovery, so five more cycles were administered, after which a moderate recovery ensued. This study further supports the efficacy of plasma exchange in the treatment of steroid unresponsive relapses in aggressive RRMS.

[Characteristics of anaemia treatment in children with chronic kidney disease]. / Posebnosti lijecenja anemije u djece s kronicnim bolestima bubrega.

In children with chronic kidney disease anaemia is seen very often. Depending of etiology and the degree of renal insufficiency is found up to 80%. The cause is mainly because of lowered production of erythropoietin in chronically damaged kidney, but also because of insufficient intake of iron and folic acid, or intake of some drugs. Erythropoietin is a hormone which is produced in kidneys. Its main role is influence on terminal differenciation of erythroid progenitors in bone marow, and also acts on eriythropoietin receptors. In most of children with chronic kidney disease plasma level of erythropoietin is lowered, or is diminished its binding on receptors in bone marrow. New era in anaemia treatment started with developement of recombinant human erythropoietin (alfa or beta epoetin) and darbepoetin alfa (somewhat different because of higher content of sialic acid in carbohydrate moiety of molecule). Last years is developed a novel epoetin which is given 1 times monthly (metoxy polietilenglycol-epoetin beta), while earlier drugs are administered 1-3 times weekly or once in 2 weeks. These drugs are called erythropoiesis stimulating agents (ESA).They are today widely used in children with chronic renal failure before dialysis, on haemodialysis or peritoneal dialysis and in patients after kidney transplantation with deterioration of graft function. Mostly are used when glomerular filtration rate is below 35 ml/min/1 .73m2, but in some patients below 50-60 ml/min/1.73 m2. Administration is via intravenous or supcutaneous route. Efficasy of subcutaenous administration is 30- 40% higher, so this route is preferred. Dosing depends (after correction of other causes of anemia) to maintain heglobin levels between 110-120 g/L, and not to exceed 130 g/L (or haematocrit levels 33-36%, and maximum levels 39%). Theyre initiation starts when hemoglobin level falls below 80% of normal values for the age. In children older than 6 years at hemoglobin <100 g/L, or hematocrit <33%. During these therapy almost allways is need for iron supplementation intravenously or peroral. Advantages of the use of ESA are multiple: there is no need for blood transfusion, and therefore lowered risk for panel reacting antibodies (PRA) or HLA antibodies. There is also lowered risk for blood transmission of viruses. The use of erythropoietin is also in anaemia of prematurity, or in some malignant diseases to enable chemotherapy or radiation procedures. Also is used in some elective surgery procedures. Its use is safe and has proven cost-benefit, with low side effects in experienced medical team. With better hemoglobin levels there is improvement of cardiovascular system, better apetite, better growth and developement of child, so as physical and mental activity and sense of well-being.

The life-threatening hemodialysis catheter heparin lock caused bleeding in a child after peritoneal catheter removal.

Hemodialysis catheter patency is regularly maintained by high-concentration heparin filling, according to manufacturer's recommendation. Surprisingly, there are only few reports on serious bleeding complications in children on dialysis. A case of serious, life-threatening hemorrhage in a child after tunneled peritoneal catheter removal because of hemodialysis catheter heparin lock flushing is described. Discussion of the literature data is presented. Further investigations are needed to develop the guidelines for pediatric dialysis catheter care, including the optimal concentration for heparin lock as the possible heparin alternatives, but until that moment, previously suggested guidelines to prevent hemorrhagic complications in dialyzed children should be emphasized.

[Clinical and histopathological characteristics of biopsy-proven renal diseases in Croatia]. / Klinicke i patohistoloske karakteristike biopsijom dokazanih bubreznih bolesti djece u Hrvatskoj.

There is little data on the spectrum of renal diseases in children in Croatia. The Croatian Society for Pediatric Nephrology has established the Registry of Biopsy-Proven Renal Diseases in an attempt to address this issue nationwide. Here we report preliminary results of a retrospective analysis of clinical and histopathological data of 565 children aged < or =17 years presenting to 9 hospitals in Croatia from 1991 to 2004, in whom kidney biopsy was performed. The most common indication for renal biopsy was nephrotic syndrome (39.1%), followed by asymptomatic proteinuria/hematuria (22.0%) and acute nephritic syndrome (17.0%). All biopsies were analysed by light-, immunofluorescent and electron microscopy. The majority of children, 552 out of 565 (92.4%), had glomerulonephritis (GN). Tubulointerstitial nephritis was found in 16 (2.8%), congenital renal parenchyma anomalies in 14 (2.5%) and vascular disease in 11 (1.9%) cases. One (0.2%) child had sarcoidosis with nephrocalcinosis. The sample was non-diagnostic in 1 (0.2%) case. Among children with GN, primary GN accounted for 70.9%, secondary GN for 16.1% and hereditary GN for 13.0% cases. The most frequent primary GN forms were focal segmental glomerulosclerosis (FSGS) (24.6%), mesangial proliferative glomerulonephritis (MEPGN) (19.2%) and IgA nephropathy (18.1%). Acute GN in resolution was found in 11.1% and minimal changes GN in 6.8% of cases. Most children with secondary GN had nephritis of Henoch-Schönlein purpura (HSP) (54.7%) and nephritis of systemic lupus erythematosus (SLE) (40.5%), while among hereditary GN Alport syndrome was most common (80.9%). In the group of children with primary GN who presented with nephrotic syndrome, most common forms were FSGS (38.5%) and MEPGN (24.0%). Minimal changes GN accounted for only 10.9% of cases. IgA nephropathy, primary or related to HSP (20.0%), FSGS (16.1%), MEPGN (12.6%) and Alport syndrome (9.7%) were the most common biopsy-proven renal diseases in Croatian children. The analysis provided data on the frequency of histological renal lesions in children in Croatia. The higher frequency of FSGS and MEPGN among Croatian children in comparison with other countries deserves further evaluation.

[Three-year-old boy--a homozygote for familiar hypercholesterolemia]. / Trogodisnji djecak--homozigot za porodicnu hiperkolesterolemiju.

Homozygous familial hypercholesterolemia (FH) is a rare autosomal dominant disorder caused by mutations in the low-density-lipoprotein (LDL) receptor gene. It occurs with a frequency of approximately 1 per million persons world-wide. Clinically, homozygous FH is associated with extremely elevated levels of LDL cholesterol and cutaneous xanthomas that develop in early childhood. These children are at risk of extremely early coronary events and death from myocardial infarction caused by premature generalized atherosclerosis. Their medical treatment is very complex, associated with various problems and complications. We describe a 3-year-old boy with clinical signs of homozygous FH (elevated LDL-cholesterol levels and xanthomas). Heterozygous hypercholesterolemia was found in his parents and some other family members. The boy has been treated with simvastatin and atorvastatin, but without reaching the treatment goals. LDL apheresis is planned as the treatment of choice for homozygous children with FH.

Complications of therapeutic plasma exchange: experience with 4857 treatments.

Plasma exchange (PE) is a technique of extracorporeal blood purification which removes large molecular weight substances from plasma. The Department of Dialysis, Zagreb University Hospital Center's database, which includes data on 509 patients, or 4857 PE treatments, was retrospectively analyzed to test the safety of PE. A total of 231 adverse reactions were recorded (4.75% of treatments). The most common complications were paresthesias (2.7%), hematoma at the puncture site (2.4%), clotting (1.7%), mild to moderate allergic reactions (urticaria; 1.6%) and bleeding (0.06%). True anaphylactoid reactions were recorded in five procedures. The incidence of severe, potentially life-threatening adverse reactions was 0.12%. The prophylactic use of calcium and potassium was responsible for a low incidence of electrolyte disturbances. There was no lethal outcome associated with PE. When carried out by experienced staff, PE is a relatively safe procedure. The use of fresh frozen plasma is associated with a higher rate of adverse reactions.

[Long-term monitoring of children with focal segmental glomerulosclerosis and a transplanted kidney]. / Dugotrajno pracenje djece s fokalnom segmentalnom glomerulosklerozom i presadenim bubregom.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS) is an important cause of nephrotic syndrome and end-stage renal disease. Children with FSGS are at a risk of recurrence of disease following renal transplantation. The rate of recurrence has been estimated to range from 15% to 50%, having a potentially detrimental course towards the loss of renal function. The factors associated with an increased probability of recurrence are not well known. PATIENTS: The authors followed 8 pediatric patients (3 girls and 5 boys) with FSGS who had undergone renal transplantation (16% of all transplanted pediatric patients) over a long period (1982-2001). The mean age of the children at the time of disease onset was 4 years and 8 months (range: 2 months-12 years). Children were monitored from 10 months to 4 years before the first dialysis. On average, the first dialysis was performed at 7 years of age (range: 12 months-16 years). Time elapsed between the first dialysis and transplantation ranged from 1 to 3 years (mean 1.5 year), and mean age at transplantation was 8 years and 6 months (range: 4-18 years). The grafts were from 2 living-related and 6 cadaveric donors. Five recipients were immunosuppressed with cyclosporin A (CsA) -steroids-azathioprine (Aza), 2 with CsA-steroids-mycophenolate mofetil (MMF), and 1 with CsA-steroids regimen. Follow-up period after transplantation ranged from 2 to 15 years (mean time 7 years and 8 months). RESULTS: Creatinine values, proteinuria range and blood pressure were monitored every 3 months after transplantation, and were as follows: creatinine 41-386 mumol/l (mean value 153 mumol/l), proteinuria 0.01-3,14 g/l (mean 0.27 g/l, median 0.03 g/l), systolic blood pressure 90-140 mm Hg (mean 110 mm Hg), diastolic blood pressure 60-90 mm Hg (mean 80 mm Hg). Two patients developed hypertension grade I and III after renal transplantation. There were 5 (0.6 per patient) acute rejection episodes. Two grafts (25%) were rejected 5 and 9 years after transplantation, but recurrence of FSGS was not confirmed by renal biopsy. CONCLUSION: Due to the small sample size no firm conclusions about recurrence of FSGS could be made. However, the fact that none of 8 children developed recurrence of FSGS after renal transplantation speaks against the relatively high recurrence rates in our pediatric population.

[Primary cytomegalovirus infection after combined cadaveric transplantation of the liver and kidney]. / Primoinfekcija citomegalovirusom nakon kombinirane kadavericne transplantacije jetre i bubrega.

Seronegative transplant recipients are at a high risk of developing primary cytomegalovirus (CMV) infection. The D+/R--constellation produces a 60%-80% probability of CMV disease. In such cases CMV prophylaxis is justified. Presentation of a 12-year old boy who developed a primary CMV infection following A combined liver-kidney transplantation; evaluation of prophylactic options and review of some difficulties in the diagnosis of CMV infection. A cadaveric liver-kidney transplantation (Tx) was done in a 12-year old boy with ESRD due to type I primary hyperoxaluria. CMV status: D+, R-; number of mismatches: 5. PRA 0; kidney cold ischemia time (CIT): 13.54 h; liver CIT: 10.10 h; immediate diuresis; Immunosuppression protocol: anti IL-2 receptor antibodies, steroids, mycophenolate mofetil (MMF); cyclosporine introduced on day 6. Over the first week, daily hemodialyses were done in order to remove oxalate deposits. Kidney and liver biopsies: no ACR, no oxalate deposits. CMV prophylaxis with ganciclovir started on day 0. Routine serology and PCR for CMV follow-up showed: pp 65, IgM and IgG, CMV. DNA (Murex CMV. DNA Hybrid Capture test 2.0): negative over the first 3 months. Day 98: CMV pp 65 positive, IgM neg, DNA neg. Day 108: pp 65 neg, IgM positive, IgG neg. CMV. DNA positive (15 x 105 copies/ml). Clinical status: except for mild Cushing, liver tests and kidney function were normal. Ganciclovir was administered intravenously (i.v.) and after 14 days continued perorally. A few days later, leukopenia with severe neutropenia (neutrophil count: 400) and right otitis media developed. MMF and ganciclovir were withdrawn for a few days and reintroduced after WBC count reconstitution. We had no possibility to monitor MMF. Day 150 pp 65 neg, IgM still positive, IgG neg. No clinical signs of infection. Liver and kidney functions normal. After liver-kidney transplantation in a CMV high-risk pediatric patient (D+/R-), asymptomatic CMV primary infection developed. Although ganciclovir prophylaxis could not prevent the infection, it was mild and delayed. Due to bone marrow suppression, discontinuation of MMF and ganciclovir was necessary. Antigenemia assay pp 65 did not correlate very well with CMV viremia so it could not be recommended as a routine test. It should be used in combination with other CMV tests.