New treatment strategies in idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) is probably due to a plasma factor of immunologic origin. This circulating factor probably interacts with the glomerular filtration barrier and is responsible for massive proteinuria. Most patients respond to steroids. However, a considerable proportion of children run a steroid dependent course. Cyclosporine A (CyA) and cyclophosphamide (CyP) have been classical treatment strategies for such cases, but specific toxicity limits the use of these drugs. Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase and thus de novo purine synthesis. Clinical trials have demonstrated the efficacy of MMF in steroid dependent NS and in children with nephrotoxicity due to prolonged CyA treatment. While MMF is a well established strategy against steroid dependency, rituximab (RTX) has emerged as a new treatment option in case of calcineurin inhibitor dependency. Non-compliance to steroid therapy can be responsible for multiple relapses and may be misinterpreted as steroid dependency and may therefore lead to unjustified increase of the immunosuppressive treatment. Triamcinolone acetonide, a long acting steroid for intramuscular injection, can replace the usual oral prednisone treatment if non-compliance is suspected. Whereas the treatment of the primary course of INS is well established, steroid dependent and steroid resistant forms are still a challenge for pediatric nephrologists. Both under-treatment with multiple relapses with disease or steroid associated morbidity on the one hand and over-treatment with specific side effects of immunosuppressive drugs may have severe consequences for the patients. The narrow path between steroid side effects and potential nephrotoxicity emphasizes the need for individualized management in severe form of INS.

Pediatric idiopathic nephrotic syndrome: treatment strategies in steroid dependent and steroid resistant forms.

Idiopathic nephrotic syndrome (INS) is defined as massive proteinuria and hypoalbuminemia associated with dyslipidemia and generalized oedema in most cases. It is thought to be due to a plasma factor of immunologic origin. Most cases are steroid responsive. However, a considerable proportion of children run a steroid dependent course. Calcineurin inhibitors and alkylating agents have been classical treatment strategies for such cases, but specific toxicity limits the use of these drugs. Mycophenolate mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase and thus de novo purine synthesis. Several uncontrolled clinical trials have demonstrated the efficacy of MMF in steroid dependent NS with or without prior use of CyP and in children with nephrotoxicity due to prolonged CyA treatment. Non-compliance to steroid therapy can be responsible for multiple relapses and may be misinterpreted as steroid dependency and may therefore lead to unjustified increase of immunosuppressive treatment. Triamcinolone acetonide, a long acting steroid for intramuscular injection, can replace the usual oral prednisone treatment if non-compliance is suspected. Whereas the treatment of the primary course of INS is well established, steroid dependent and steroid resistant forms are still a challenge for pediatric nephrologists. Both under-treatment with multiple relapses with disease or steroid associated morbidity on the one hand and over-treatment with specific side effects of immunosuppressive drugs may have severe consequences for the patients.

[Stop of antibiotic prophylaxis in mild/moderate grade vesico-ureteral reflux]. / Arrêt de l'antibioprophylaxie urinaire dans les reflux vésico-urétéraux de grade I, II ou III.

UNLABELLED: Vesicoureteric reflux (VUR) is found in about 30 % of children with pyelonephritis (PN). It has been identified as a risk factor for the development of urinary tract infections, renal scars, hypertension and chronic renal failure but this risk is considerably smaller than previously assumed. Currently the therapeutic option was to use an antibiotic prophylaxis in order to keep the urinary tract sterile in order to prevent pyelonephritis and new renal scars. The review of the available data has shown that the antibiotic prophylaxis therapy is subject to discussion. The aim of this study was to evaluate the follow up of children with low-grade reflux before and after stopping the urinary antibiotic prophylaxis as soon as they became toilet-trained. METHODS: Fifty-eight children with low-grade reflux (grade I, II, III) were enrolled in this study. The follow up ranged from October 2002 till February 2007. The children who have not attained bladder control received antibiotic prophylaxis. This treatment was stopped as soon as they became toilet-trained. The presence of urinary tract infection (UTI) was considered in case of unexplained fever and urinalysis and urine culture were performed. RESULTS: VUR, mainly grade II, was discovered at a median age of 16 months. The prophylaxis was stopped at a median age of 40 months. The follow up after stopping the antibacterial prophylaxis was 27 months. Under treatment 2 pyelonephritis occurred, without treatment 2 pyelonephritis and 3 cystitis were diagnosed. At the end of the follow up, the grade of reflux decreased in half of the cases and disappeared in 3 cases. CONCLUSION: By stopping the urinary antibiotic prophylaxis in children with mild/moderate grade VUR when they became toilet-trained, there is no increase of the incidence of UTI, pyelonephritis. This study does not support the role for urinary antibiotic prophylaxis in preventing the recurrence of pyelonephritis.

[Abnormalities of hepatocyte nuclear factor (HNF)-1beta: biological mechanisms, phenotypes, and clinical consequences]. / Les anomalies de l'hepatocyte nuclear factor (HNF)-1beta : mécanismes biologiques, phénotypes et conséquences cliniques.

The hepatocyte nuclear factor-1beta encoded by the TCF2 gene plays a role in the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for maturity-onset diabetes of the young type 5, associated with renal manifestations. Several studies have shown that TCF2 mutations are involved in restricted renal phenotypes. In a recent study, TCF2 anomalies were detected in one third of patients with renal anomalies such as renal cysts, hyperechogenicity, hypoplasia, or single kidneys. Most patients have a complete deletion of the TCF2 gene. With de novo TCF2 anomalies, deletions were the most frequent anomaly. TCF2 anomalies were significantly associated with bilateral renal anomalies and bilateral cortical cysts. However, no genotype-phenotype correlation could be detected. The prenatal phenotype of TCF2 anomalies is mainly bilateral hyperechogenic kidneys. Abnormal renal function, detected in about one third of patients, was independent of the TCF2 genotype. The best parameter to predict renal outcome remains sonographic evaluation. However, progression of the TCF2 phenotype is common. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. Adequate metabolic follow-up of pediatric patients with a restricted renal phenotype has not yet been defined and consideration of prenatal diagnosis remains extremely difficult given the extremely large phenotypic variability within the same family.

Successful anti-TNFalpha treatment in a child with posttransplant recurrent focal segmental glomerulosclerosis.

Posttransplant recurrence of focal and segmental glomulosclerosis (FSGS) occurs in approximately 30% of patients, and remains after uncontrolled despite increased immunosuppression and plasma exchanges (PE) in approximately 30% of cases. New immunosuppressive drugs might then be warranted. We report the case of a 15-year-old boy with FSGS leading to end-stage renal disease (ESRD) who presented with an early posttransplant recurrence of disease. Reinforced immunosuppression and PE resulted in partial and transient disease control, but proteinuria significantly decreased with anti-TNFalpha treatment (infliximab then etanercep). This is the first case report of successful anti-TNFalpha treatment despite a constant high activity of FSGS, as demonstrated by relapse after discontinuation of anti-TNFalpha agents.

Abdominal manifestations in childhood-onset systemic lupus erythematosus.

BACKGROUND: Childhood-onset lupus erythematosus is a rare disorder of unknown origin. OBJECTIVES: To describe the frequency of gastrointestinal manifestations at presentation of systemic lupus erythematosus SLE and at follow-up, and discuss the specific causes of these manifestations. METHODS: Medical records of 201 patients with childhood-onset SLE followed up in French paediatric nephrological, haematological and rheumatological centres were reviewed and abstracted for gastrointestinal manifestations. RESULTS: Gastrointestinal involvement was recorded in 39 (19%) children. The median (range) age at the time of initial gastrointestinal manifestations was 11.3 (4.5-16) years. Gastrointestinal symptoms were present at or occurred within 1 month after diagnosis in 32% patients. Abdominal pain was the most frequent symptom, present in 34 (87%) patients. It was mostly related to lupus involvement, especially ascites (n = 14) and pancreatitis (n = 12), more rarely to treatment-induced events (n = 1) or infection (n = 1) and never to events unrelated to SLE. Three children with surgical abdomen underwent a laparotomy before SLE was diagnosed, with a final diagnosis of lupus peritonitis and lupus acalculous cholecystitis. C reactive protein values were <40 mg/l in all but two patients who had surgical abdomen. Abdominal ultrasonography and computed tomography scans were abnormal in 58% and 83% of the evaluated patients, respectively. Corticosteroids, associated with intravenous cyclophospamide in eight patients, led to complete remission of gastrointestinal involvement in 30 of 31 treated patients. CONCLUSION: Gastrointestinal involvement is common in children with SLE, and is mainly due to primary lupus involvement. Corticoidsteroid treatment should be promptly considered in children with lupus presenting with abdominal pain after infectious disease; side effects of treatment and intestinal perforation have been excluded.

Rituximab therapy for childhood-onset systemic lupus erythematosus.

OBJECTIVE: To describe the safety and efficacy of rituximab in the treatment of childhood-onset systemic lupus erythematosus (SLE). STUDY DESIGN: We conducted a French multicenter retrospective study of childhood-onset SLE treated with rituximab. RESULTS: Eleven girls with severe SLE, including 8 girls with class IV or V lupus nephritis, 2 girls with severe autoimmune cytopenia, and 1 girl with antiprothrombin antibody with severe hemorrhage, were treated with rituximab. The mean age at onset of rituximab treatment was 13.9 years. Patients received 2 to 12 intravenous infusions of rituximab (350-450 mg/m2/infusion), with corticosteroids. Six patients also received different standard immunosuppressive agents, including Cyclophosphamide (2 patients). Remission was achieved in 6 of 8 patients with lupus nephritis and in the 2 patients with autoimmune cytopenia. Steroid therapy was tapered in 5 patients who responded to treatment, and low-dose prednisone treatment was maintained in 1 patient. The mean follow-up period was 13.2 months (range, 6-26 months), and remission lasted in all who patients who responded to treatment, except 1 patient who was successfully retreated with a second course of rituximab. Anti-double-stranded DNA antibody levels decreased in 6 of 11 patients, and anticardiolipin antibody levels decreased in 3 of 4 patients. Severe adverse events developed in 5 patients. Effective depletion of peripheral blood B cells was observed in 7 of 8 patients who were examined, and this paralleled the remission. CONCLUSION: Rituximab may be an effective co-therapy; however, further investigations are required because severe adverse events occurred in 45% of the patients in this study.

From humoral rejection to generalized thrombotic microangiopathy--role of acquired ADAMTS13 deficiency in a renal allograft recipient.

A 9-year-old renal transplant recipient presented with elevated serum creatinine levels 4 years post-transplant renal biopsy revealed humoral rejection including lesions suggestive for thrombotic microangiopathy (TMA). He received methylprednisolone pulses followed by a normalization of serum creatinine. Two more steroid responsive acute rejection episodes occurred. Two months later he presented rapidly progressive life threatening symptoms including bilateral pyramidal syndrome and hemoptysis. Serum haptoglobin became undetectable at this time and platelet count decreased (70000/microl), suggesting TMA. Cerebral MRI revealed generalized ischemic white matter lesions. ADAMTS13 activity decreased to < 5%. Daily plasma exchanges (PE) resulted in immediate improvement. All attempts to discontinue PE were unsuccessful. Transplantectomy resulted in normalization of generalized symptoms, hemolysis and ADAMTS13 activity (110%). Multi-organ involvement has never been reported in acquired ADAMTS13 deficiency post-transplant. Rapid resolution after transplantectomy might suggest that renal TMA was responsible for acquired ADAMTS13 deficiency and thereby triggered the generalization of TMA lesions.

[Renal complications of non-steroidal anti-inflammatories]. / Complications rénales des anti-inflammatoires non stéroïdiens.

INTRODUCTION: Non-steroidal antiinflammatory drugs (NSAIDs) are known to have adverse effects on kidney function. Situations with stimulated renin-angiotensin system (RAS) like volume depletion or preexisting chronic renal failure predispose to acute renal failure (ARF) via inhibition of prostaglandin synthesis by NSAIDs. To date NSAIDs are frequently used as antipyretic drugs even in situations predisposing to ARF. PATIENTS: Within 20 months seven children presenting with diarrhea and/or vomiting and fever were treated with therapeutic doses (11.5-32 mg/kg per day) of ibuprofen for 1-3 days before developing ARF. Maximum plasma creatinine levels were 180-650 pmol/l. One patient required emergency dialysis for hyperkalemia, uremia, and hyperphosphatemia. After cessation of NSAID treatment and rehydration all patients recovered completely with a normalized creatinine level after 3-9 days. Once the acute phase is controlled long-term outcome is excellent. CONCLUSION: NSAIDs are potentially dangerous in situations with, even moderate, volume depletion.

Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. German Study Group for Growth Hormone Treatment in Chronic Renal Failure.

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8-19.0) years] with CRF [glomerular filtration rate 26.6 (7.0-67.4) ml/min per 1.73 m2], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080+/-268 ng/ml; pubertal 989+/-299 ng/ml) compared to healthy prepubertal controls (265+/-73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361+/-120 ng/ml vs 282+/-75 ng/ml in controls) nor pubertal CRF children (478+/-165 ng/ml vs 491+/-80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=-0.39, P<0.001). In prepubertal children, IGFBP-4 levels were inversely correlated with standardized height (r=-0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II(r=0.42, P<0.001)and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=-0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of TGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor.